CA2024306A1 - Cyclohexanol derivatives, production and use thereof - Google Patents
Cyclohexanol derivatives, production and use thereofInfo
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- CA2024306A1 CA2024306A1 CA002024306A CA2024306A CA2024306A1 CA 2024306 A1 CA2024306 A1 CA 2024306A1 CA 002024306 A CA002024306 A CA 002024306A CA 2024306 A CA2024306 A CA 2024306A CA 2024306 A1 CA2024306 A1 CA 2024306A1
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- dimethyl
- epoxy
- hexenyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
- C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
- C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds
- C07D303/23—Oxiranylmethyl ethers of compounds having one hydroxy group bound to a six-membered aromatic ring, the oxiranylmethyl radical not being further substituted, i.e.
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
- C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
- C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/34—Compounds containing oxirane rings with hydrocarbon radicals, substituted by sulphur, selenium or tellurium atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/36—Compounds containing oxirane rings with hydrocarbon radicals, substituted by nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
Abstract of the Disclosure The present invention relates to a compound of the formula:
wherein A is halogen, N(O)mR1R2, N?R1R2R3?X?, S(O)nR1 or S?(O)mR1R2?X? where R1,R2 and R3 are each optionally substituted hydrocarbon or heterocyclic group, X? is a counter anion; m is an integer of 0 or 1; n is an integer of 0 to 2; R1 and R2 may form a nitrogen-containing or a sulfur-containing heterocyclic ring, which may further form a condensed ring, with the adjacent nitrogen atom or sulfur atom, and these nitrogen-containing or sulfur-containing heterocyclic rings may have substituents, B is O or NR4 where R4 is hydrogen or an optionally substituted lower alkyl or aryl group, D is 2-methyl-1-propenyl group or isobutyl group, and E is hydrogen, an optionally substituted hydrocarbon or an optionally substituted acyl group;
provided that, when A is chlorine, E is an optionally substituted hydrocarbon or acyl excepting dinitrobenzoyl, a salt thereof, production and use thereof.
The novel cyclohexanol derivatives of the present invention have angiogenesis inhibiting activity and anti-tumor activity, and they are used as anti-rheumatic agents, therapeutic agents of psoriasis, therapeutic agents of diabetic retinopathy and anti-tumor agents.
wherein A is halogen, N(O)mR1R2, N?R1R2R3?X?, S(O)nR1 or S?(O)mR1R2?X? where R1,R2 and R3 are each optionally substituted hydrocarbon or heterocyclic group, X? is a counter anion; m is an integer of 0 or 1; n is an integer of 0 to 2; R1 and R2 may form a nitrogen-containing or a sulfur-containing heterocyclic ring, which may further form a condensed ring, with the adjacent nitrogen atom or sulfur atom, and these nitrogen-containing or sulfur-containing heterocyclic rings may have substituents, B is O or NR4 where R4 is hydrogen or an optionally substituted lower alkyl or aryl group, D is 2-methyl-1-propenyl group or isobutyl group, and E is hydrogen, an optionally substituted hydrocarbon or an optionally substituted acyl group;
provided that, when A is chlorine, E is an optionally substituted hydrocarbon or acyl excepting dinitrobenzoyl, a salt thereof, production and use thereof.
The novel cyclohexanol derivatives of the present invention have angiogenesis inhibiting activity and anti-tumor activity, and they are used as anti-rheumatic agents, therapeutic agents of psoriasis, therapeutic agents of diabetic retinopathy and anti-tumor agents.
Description
CYclohexanol Derivativesr Production and Use Thereof TECHNICAL FIELD
This invention relates to novel cyclohexanol derivatives and their use.
BACRGROUND TECHNOLOGY
Angiogenesis is deeply concerned with occurrence of pathological processes o~ various in1ammatory diseases (rheumati.c diseases, psoriasis, etc.), diabetic retinopathy, tumors, etc. Therefore, it has been considered that inhibition of angiogenesis has a connection with therapy and prophylaxis of these diseases and several groups have searched for substances capable of inhibiting angiogenesis. For example, mention is made of research works for application of Protamine by Taylor [Taylor, S, et al., Nature, 297, 307 (1982)] and for use of heparin in the presence of cortisone by Folkman et al. [Folkman, J. et al., Science, 221, 719 (1983)]. Furthermore, patent applications have been filed directed to ascorbic acid ether and its re].ated compounds (JP-A-131978/1983) or polysaccharide sulfate DS4125 (JP-~-119500/1988) as compounds showing activity of inhibiting angiogenesis.
However, the activities of these compounds are not sufficiently satisfactory, and compounds having more satisfactory activity are desired.
OBJECT OF THE INVENTION
The object of the present invention lies in providing novel compounds having an action of inhibiting angiogenesis and an anti-tumor action, whose toxicity to hosts is low.
To attain the above-mentioned object, the present inventors have conducted searches for various compounds and evaluation of them. As a result, they found that cyclohexanol derivatives, chemically derived from fumagillol, hydrolysate of fumagillin which has been 2 ~
known as an antibiotic agent and an antiprotozoal agent, have a superb action of inhibiting angiogenesis and an anti-tumor action, and that they are less Loxic to hosts, thus the present invention has been accomplished.
SUMMARY_OF ~HE INVENTION
More specifically, the present invention i9 to provide A compound represented by the formula:
HO~CH2D
~"1"~
I Ol~e B--E
wherein A i.s halogen, N(O)mR~R2, N~RlR2R~ X~, S(O)nR~ or S~(O)mRlR2-X~ (where Rl,R2 and R3 are each optionally substituted hydrocarbon group or heterocyclic group, X~
is a counter anion; m is an integer of~0 or 1; n is an integer of 0 to 2; Rl and R2 may form a nitrogen-containing or a sulfur-containing heterocyclic ring, which may further form a condensed ring, with the `adjacent nitrogen atom or sulfur atom, and these nitrogen-containing or sulfur-containing heterocyclic rings may have substituents); B is O or NR4 (where R4 is hydrogen or an optionally substituted lower alkyl or aryl group); D is 2-methyl-1-propenyl group or isobutyl group; and E is hydrogen, an optionally substituted hydrocarbon group or an optionally substituted acyl group; provided that, when A is chlorine, E is an optionally substituted hydrocarbon group or acyl ~ excepting dinitrobenzoyl, or a sàlt thereof, its production, and an antitumor agent containing a compound represented by the formula:
2 ~
NO C~l a C}J 2 D
f~/
~O~le (I') B--E' wherein A is halogen, N(O)mR~R2, N~RIR2R3-X~, S(O)nR~ or S~(O)mRIR2~X~ (where Rl,R2 and R3 are each optionally substituted hydrocarbon group or heterocyclic group, X~
is a counter anion; m is an integer of 0 or 1; n is an integer of 0 to 2; Rl and R2 may form a nitrogen-containing or a sul~ur-containing heterocyclic ring, which may further form a condensed ring, with the adjacent nitrogen atom or sulfur atom, and these nitrogen-containing or sulfur-containing heterocyclic rings may have substituents); B is O or NR4 (where R4 is hydrogen or an optionally substituted lower alkyl or aryl group); D is 2-methyl~1-propenyl group or isobutyl group; and E' is hydrogen, an optionally substituted hydrocarbon group or an optionalIy substituted acyl group, or a salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
In the above-mentioned formulae (I) and (I'), the halogen shown by A includes fluorine, chloriner bromine and iodine.
Examples of the hydrocarbon groups of the - optionally substituted hydrocarbon groups shown ~y Rl, R2 or R3 include straight-chained or branched Cl6 alkyl groups (e.g. methyl, ethyl, propyl, isopropylj butyl, isobutyl, sec-butyl, pentyl, isopentyl, hexyl, etc.), C2-6 alkenyl groups (e.g. vinyl, allyl, 2-butenyl, methylallyl, 3-butenyl, 2-pentenyl~ 4-pentenyl, 5-hexenyl, etc.), C26 alkynyl groups (e.g. ethynyl, propargyl, 2-butyn-l-yl, 3-butyn2-yl, 1-pentyn-3-yl, 3-:
- 4 - 2~
pentyn-].-yl, 4-pentyn-2-yl, 3-hexyn-1-yl, etc.), C36 cycloalkyl groups (e.~. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), C~6 cycloalkenyl groups (e.g. cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, etc.), C71~ aralkyl g~oups (e~g.
benxyl, l-phenethyl, 2-phenethyl, etc.), and C6~0 aryl groups (e.g. phenyl, naphthyl, etc.).
Examples of the heterocyclic groups of the optionally substituted heterocyclic groups shown by Rl, R2 or R3 include 5- or 6-membered heterocyclic groups containing 1 to 4 hetero-atoms such as nitrogen, oxygen, sulfur, etc. (e.g. 2-furyl, 2-thienyl, 4-thiazolyl, 4~imidazolyl, 4-pyridyl, 1,3,4-thiadiazol-2 yl, 1-methyl-5-tetrazolyl, etc.). These heterocyclic groups may form bicyclic condensed rings by condensation with 5- or 6-membered ring such as benzene, pyridine, cyclohexane, etc. (e.g. 8-quinolyl, 8-purinyl, etc.) Examples of the nitrogen-containing heterocyclic groups which may be formed by Rl and R2 together with the adjacent nitrogen atom include 4- to 7-membered nitrogen-containing he-terocyclic groups (e.g.
pyrrolidin-l-yl, piperazino, morpholino, 4-methylpiperazin-1-yl, etc.).
Examples of the sulfur-containing heterocyclic groups which may be formed by Rl and R2 together with the adjacent sulfur atom include 4- to 7-membered - sulfur containing heterocyclic groups (e.g.
tetrahydrathiophen-1-yl, 1,4-thioxan-l-yl~ etc.).
The nitrogen-containing or sulfur-containing heterocyclic groups which may be formed by Rl and R2 together with the adjacent nitrogen atom or sulfur atom may be condensed with a 5- or 6-membered cyclic group (e.g. benzene, pyridine, pyrazine, pyridazine, cyclohexane, cyclohexene, etc.) to form bicyclic condensed rings (e.g. isoindolin-2-yl, 2-isoquinolyl, 2 ~ 2 '~
1,3-dihydrobenzo[c]thiophen-2-yl, 2,3-dihydrobenzo[b]thiophen-1-yl, 1,3,3a,4,7,7a-hexahydrobenzo[c]thiophen-2-yl, perhydrobenzo[c]th.iophen 2-yl, 3,4-dihydro-lH-2-benzopyran-2-yl, 3,4-dihydro-2H-l-benzopyran-1-yl, 1,2,~,5-tetrahydro-3-benzothiepin-3~yl t 1,3-dihydrothieno[3,4-c]pyridin-2-yl, S,7-dihydrothieno[3,4-b]pyrazin-6-yl, 5,7-dihydrothieno[3,4-d]pyridazin-6-yl, etc.) Examples of the lower alkyl groups of the optionally substituted lower alkyl groups shown by R4 include Cl6 alkyl groups (e.g. methyl, ethyl, propyl, isopropyl, butyl, is~butyl, sec-butyl, pentyl, isopentyl, hexyl, etc.).
As the aryl groups of the optionally substituted aryl groups shown by R4, mention is made of C6~10 aryl groups (e.g. phenyl, naphthyl, etc.).
As the optionally substituted hydrocarbon groups shown by E or E', mention is made of those specifically described above as the optionally substituted hydrocarbon groups shown by Rl, R2 and R3.
As the optionally substituted acyl groups shown by E or E', mention is made of the residues of acids such as carboxylic acid acyl, sulfonic acid acyl, carbamoyl, thiocarbamoyl, sulfamoyl, etc., and examples of them include respectively optionally substituted alkanoyl, aroyl, heterocyclic carbonyl, carbamoyl, thiocarbamoyl, arylsulfonyl, alkylsulfonyl, sulfamoyl, alkoxycarbonyl, aryloxycarbonyl, etc.
As the alkanoyl groups of the above-mentioned optionally substîtuted alkanoyl groups, mention is made of Cl10 alkanoyl groups (e.g. formyl, acetyl, propionyl, isopropionyl, butyryl, pentanoyl, hexanoyl, etc.).
As the aroyl groups of the optionally substituted aroyl groups, mention is made of C7l0 aroyl groups - 6 - 2~2~t~
(e.g. benzoyl, 1-naphthoyl, 2-naphthoyl, etc.).
As the heterocyclic carbonyl groups in the optionally substituted heterocyclic carbonyl groups, mention is made of 5- or 6-membered heterocyclic carbonyl groups containing 1 to 4 hetero-atoms such as nitrogen, oxygen, sulfur, etc. (e.g. ~-~uroyl, 2-thenoyl, nicotinoyl, isonicotinoyl, etc.).
As the arylsulfonyl groups of the optionally substituted arylsulfonyl groups, mention is made of C6 lo arylsulfonyl groups (e.g. benzenesul~onyl, 2-naphthylsulfonyl, etc.).
As the alkylsulfonyl groups of the optionally substituted alkylsulfonyl groups, mention is made of Cl6 alkylsulfonyl groups te.g. methylsulfonyl, ethylsulfonyl, etc.).
As the alkoxycarbonyl groups of the optionally substituted alkoxycarbonyl groups, mention is made of C27 alkoxycarbonyl groups (e.g. methoxycarbonyl, ethoxycarbonyl, isobutoxycarbonyl, etc.).
As the aryloxycarbonyl groups of the optionally substituted aryloxycarbonyl groups, mention is made of C7il aryloxycarbonyl groups (e.g. pheno~ycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl, etc.
The respectively optionally substituted hydrocarbon groups or hetarocyclic groups shown by Rl, R2 or R3, the nitrogen-containing or sulfur-containing - heterocyclic groups which may be ~ormed by Rl and R2 together with the adjacent nitrogen atom or sulfur atom and may form condensed ring, the respectively optionally substituted lower alkyl groups or aryl groups shown by R4, and the respectively optionally substituted hydrocarbon groups or acyl groups (e.g.
alkanoyl group, aroyl group, heterocyclic carbonyl group, carbamoyl group, thiocarbamoyl group, arylsulfonyl group, alkylsulfonyl group, sulfamoyl group, alkoxycarbonyl group or aryloxycarbonyl group) - 7 - 2 ~ t~
shown by E or E' may have 1 to 3 substituents at any posi.tions possibly substituted.
Examples of these substituents include Cl6 alkyl groups (e.g. methyl, ethyl, propyl, isopxopyl, butyl, sec-butyl, pentyl, isopentyl, hexyl, etc.), C26 alkenyl groups te.g. vi.nyl, allyl, 2-butenyl, methylallyl, 3-butenyl, 2-pentenyl, 4-pentenyl, S-hexenyl, etc.), C26 alkynyl groups (e.g. ethynyl, propargyl, 2-butyn-1-yl, 3-butyn-2-yl, 1-pentyn-3-yl, 3-pentyn-1-yl, 4-pentyn-2-yl, 3-hexyn-1-yl, etc.), C36 cycloalkyl groups (cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), C36 cycloalkenyl groups (e.g. cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, etc.), C6l0 aryl groups (e.g. phenyl, naphthyl, etc.), amino, Cl6 alkylamino groups (e.g. methylamino, ethylamino, isopropylamino, etc.), diCI6 alkylamino groups (e.g.
dimethylamino, diethylamino, etc.), azido, nitro, halogen (e.g. fluorine, chlorine, bromine, iodine, etc.)~ hydroxyl, Cl4 alkoxy groups (e.g. methoxy, ethoxy, etc.), C6l0 aryloxy groups (e.g. phenoxy, naphthyloxy, etc.), Cl6 alkylthio groups (e.g.
methylthio, ethylthio, propylthio, etc.), C6l0 arylthio groups (e.g. phenylthio, naphthylthio, etc.), cyano, carbamoyl groups, carboxyl groups, C14 alkoxycarbonyl groups (e.g. methoxycarbonyl, ethoxycarbonyl, etc.), C7ll aryloxycarbonyl groups (e.g. phenoxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl, etc.), carboxy Cl4 alkoxy groups (e.g. carboxymethoxy, 2-carboxyethoxy, etc.~, C16 alkanoyl groups (e.g. formyl, acetyl, propionyl, isopropionyl, butyryl, pentanoyl, hexanoyl, etc.), C7l1 aroyl groups (e.g. benzoyl, 1-naphthoyl, 2-naphthoyl, etc.), C6l0 arylsulfonyl groups (e.g. benzenesulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, etc.), Cl6 alkylsulfinyl groups (e.g.
methylsulfinyl, ethylsulfinyl, etc.), C6l0 arylsulfinyl groups (e.g. benzenesulfinyl, 1-naphthylsulfinyl, 2-- 8 - 2~
naphthylsulfinyl, etc.), Cl6 alkylsulfonyl groups (e.g.
methylsulfonyl, ethylsulfonyl, etc.), 5- or 6-membered heterocycllc groups containing 1-4 hetero~atoms such as nitrogen, oxygen, sulfur, etc. (e.g. 2-furyl, 2-S thienyl, ~-thiazolyl, 4-imidazolyl, 4-pyridyl, l,3,4-thiadiazol-2-yl, 1-methyl-5-tetrazolyl, etc.), 5- or 6-membered heterocyclic carbonyl groups containing 1 to 4 hetero-atoms such as nitrogen, oxygen, sulfur, etc.
(e.g. 2-furoyl, 2-thenoyl, n:icotinyl, isonicotinyl, etc.), and 5- or 6-membered heterocyclic groups containing 1 to 4 hetero-atoms such as nitrogen, oxygen, sulfur, etc., (e.g. 4-pyridylthio, 2-pyrimidylthio, 1,3,4-thiadiazol-2-ylthio, l-methyl-5-tetrazolylthio, etc.) and the heterocyclic thio groups lS may be fused with benzene ring to form bicyclic condensed ring thio groups (e.g. 2-benzothiazolylthio, 8-quinolylthio, etc.). And, when ~ or E~ each stands for di-substituted carbamoyl group, thiocarbamoyl group or sulfamoyl group, it may form, taken together with the nitrogen atom of the carbamoyl group, thiocarbamoyl group or sulfamoyl group, a nitrogen-containing heterocyclic group (e.g. pyrrolidin-1-yl, piperidino, morpholino, piperazin-l-yl, 4-methylpiperazin-1-yl, 4-phenylpiperazin-yl, etc.
And, the substituants in the respectively optionally substituted hydrocarbon groups or heterocyclic groups shown by Rl, R2 or R3, the substituents in the nitrogen-containing or sulfur-containing heterocyclic groups, which may be formed by Rl and R2 together with adjacent nitrogen atom or sulfur atom, which may further form condensed ring, the substituents in the respectively optionally substituted lower alkyl groups or aryl groups shown by R4, and the substituents in the respectively optionally substituted hydrocarbon groups, alkanoyl groups, aroyl groups, heterocyclic carbonyl groups, carbamoyl groups, 2~3g~;
thiocarbamoyl groups, aryl sulfonyl groups, alkyl sulfonyl groups, sulfamoyl groups, alkoxy carbonyl ~roups or aryloxy carbonyl groups, which are shown by E
or E', may further have 1 to 3 substituents at subst.i.tutive positions.
As these substituents, use is made of those as exemplifi.ed by the substituents in the respectively optionally substituted hydrocarbon groups or heterocyclic groups shown by Rl, R2 or R3, the substituents in the nitrogen-containing or sulfur-containing heterocyclic groups, which may be formed by Rl and R2 together with adjacent nitrogen atom or sulfur atom, which may further form condensed ring, the substituents in the respectively optionally substituted lower alkyl groups or aryl groups shown by R4, and the substituents in the respectively optionally substituted hydrocarbon groups, alkanoyl groups, aroyl groups, heterocyclic oarbonyl groups, carbamoyl groups, thiocarbamoyl groups, aryl sulfonyl groups, alkyl sulfonyl groups, sulfamoyl groups, alkoxy carbonyl groups or aryloxy carbonyl groups, which are shown by E
or E', as they are.
Examples of the counter anion shown by X~ include halogen ion (e.g. iodide ion, bromide ion, chloride ion, etc.), sulfate ion, phosphate ion, nitrate ion, perchlorate ion, tetrafluoroborate ion, methanesulfonate ion, p-tolylsulfate ion, benzenesl.lfate ion, hydroxyl ion, carboxyl ion of organic acid (oxalate ion, maleate ion, fumarate ion, succinate ion, citrate ion, lactate ion, trifluoroacetate ion, lactobionate ion, acetate ion, propionate ion, tartrate ion, ethyl succinate ion, etc.).
While the compound (I) or (I~) has the asymmetric center in the molecule and has optical acti~ity, its absolute structure is based on fumagillol employed as 2 ~ 2 ~
the starting material. This means that the absolute structure is in agreement with that o fumagillol. In the description of manner o~ linkage of the substituents on the cyclohexane ring, ~'''' shows a-lin~age, ~ show ~-linkage, and shows the ca~e where the linkage may be either ~-type or ~-type.
When the compound o~ this in~ention has, in its molecule, an acid substituent (e.g. carboxyl, etc.) or a basic substituent (e.g. amino, a lower alkylamino, a di-lower alkylamino, a nitrogen-containing heterocyclic group, etc.), it can be used as a physiologically acceptable salt as well. Examples of the physiologically acceptable salt include salts with inorganic bases, salts with organic bases, and salts with basic or acid amino acids. E~amples of inorganic bases include alkali metals (e.g. sodium, potassium, etc.) and alkaline earth metals (e.g. calcium, magnesium, etc.), examples of organic bases include trimethylamine, triethylamine, pyridine, picoline, N,N-dibenzylethylenediamine, ethanolamine, diethanolamine,tris-hydroxymethylaminomethane, dicyclohexylamine, etc., examples of inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., examples of organic acids include formic acid, acetic acid, trifluoroacetic acid, oxalic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and exampIes of basic or acid amino acids include arginine, lysine, ornithine, aspartic acid, glutamic acid, etc. Among these salts, those with bases (i.e. salts with inorganic bases, salts with organic bases, salts with basic amino acids) mean salts which can be formed with the carboxyl group in the substituents of the compound (I) and (I'), and salts with acids (i.e. salts with inorganic acids, salts with organic acids, salts with acid amino acids) g ~ean salts -~hich can oe ~^or~ed with amino group, a lower al.~ l-amino group, di-lower alkylamino group, a nitro~en-contain-~g heterocyclic group, etc. in the substituents of the compound (I).
~ d, when the compound (I) and (I') have intramolecularlv a di-lower alkyl~mino qroup, a nitroyen-containing heterocycl'c group or a nitroyen-containing aromatic heterocyclic group, the nitrogen atom in these suhstituents may rurther be alkylated to form a quaternay ammonio group (e.g. trimethylammonio, N-methyl-pyridinio, N-methylpyrrolidin-L-ylio, etc.), and, as the counter anion, mention is made of counter anion similar to that shown by the afore-mentioned X .
In the compound (I) and (I'), A is preferably N(O)mRlR , N RlR2R3-X , S(O)nRl and S (O)mRlR2- X , especially S RlR X
wherein Rl and R2 are hydrocarbon group and X is halogen.
As B, O or N~ is preferable, as D, 2-methyl-1-propenyl is preferable, and, as E or E', substituted carbamoyl is preferable.
When A is -S RlR X , a particularly preferred value for -S RlR2 is 1,3-dihydrobezo[c~thiophen-2-ylio, tetrahydrothiophen-l -ylio, 1,3,3a,4,7,7a-hexahydrobenzo[c]thiophen-2-ylio, dimethyl-sulfonio, ethylmethylsulfonio, benzylmethylsulfonio, (2-propynyl) methylsulfonio, allylmethylsulfonio, (4-bromobenzyl)methylsulfonio, (4-chlorobenzyl)methylsulfonio, (4-fluorobenzyl)methylsultonio, (4-methylbenzyl)methylsulfonio, (3-bromobenzyl)methylsulfonio, (2-bromobenzyl)methylsulfonio, diallysulfonio or dibenzylsulfonio.
When A is -SR2, -SOR2 or -S02R2, a preferred value for A
is phenylthio, l-naphthylthio, 8-quinolylthio, methylthio, phenyl-sulfinyl, methylsulfinyl, methylsulfonyl, 4-pyridylthio, ~-methyl-4-pyridiniothio, 2-pyrimidinylthio, ethylthio, allylthio, 2~ 3~
- :~- 2'~ -3a 2-hydro~benzylthio, 2-me-hanesulfonylcxybenzylth-o, 4-hyd-oxybu.-~-lflthio, ~-methanesulfonyloxybutyrylthio, 2-chloromethylbenzilth~o, 2-hvdroxyethylthio, 4-chlorobenzylthio, 4-bromobenzylthio, ~-flu-orobenzylthio, 4-methylbenzylthio, 3-bromobenzylthio, 2- bn~x~
benzylthio, 3,4,5,6-tetrafl~oro-2-hydroxymethylbenzylthio, 3,~,5,6-tetrafluoro-2-methanesulfonyloxybenzylthio or 6-hydroxymethyl-3-cyclohexenylmethylthio~
A class of compounds within the scope of the formula (I) are those in which: B is O and E is hydrogen, C1 l~alkanoyl, C7 10aroyl, C2 7alkoxycarbonyl, Cl 6alkylsulfonyl, C7_11aryloxy-carbonyl or carbamoyl which may be ~ubstituted by C3 6alkenyl, Cl_6alkyl, or C6 1Oaryl, Cl 6alkanoyl ~which may further be substituted by halogen, Cl_6alkylthio, C7_11aralkylthio, C6_10aryl-thio, benzothiazolylthio or quinolylthio).
A particularly preferred group for the substituted carbamoyl group includescarbamoyl, chloroacetylcarbamoyl, acryloyl-carbamoyl, methacryloxylcarbamoyl, 3-chloro-2-methylpropionyl-carbamoyl, phenylthioacetylcarbamoyl, 1-naphthylthioacetylcarba-moyl, 8-quinolylthioacetylcarbamoyl, l-naphthylcarbamoyl, 2-benzothiazolylthioacetylcarbamoyl, morpholinocarbonyl, chloro-methylcarbamayl, 2-chloroethylcarbamoyl, (2~benzothiazolylthio) thioacetylcarbamoyl, methylthioacetylcarbamoyl and benzylth o-acetylcarbamoyl.
Another class of compounds within the scope of the formula (I) are those in which: B is -NH, and ~ is the acyl. A particu-larly preferred acyl for E in this group is the carbamoyl mentioned above. An especially preferred group for -B-E in this class is N chloroacetylureido.
~ 3 ~
llb 24205-885 The compound of this invention represented by the general formula (I) can be produced by employing, as the starting material, fumagillol, which is the hydrolysate of fumagillin produced by microorganism, [Tarbell, D. S. et al., ~J. Am. Chem. Soc.) 83, 3096 (1961)]. The production method is described in detail as follows.
A compound (I), wherein the manner of linkage of the cyclohexane ring with B is ~-type, B is O and D is 2-methyl-1-isopropenyl, can be produced as the intermediates or the end products shown by (IV) ~ (XIII) to be obtained by conducting the reaction shown by the following scheme 1.
-- 12 -- 2 ~ 2 ~
(Scheme ].) ~J `~
OH OCH ~ \
llonclionhtopl / iulllnillllol(ll) \ Itonclln~Rtop~i Itoncllo-~ nlop 3 \~
~/llonclin~ Rl~p7 Y~ y~ Z~
H ~ ~ H9~
J. llonclioll ololl 5 i~i nonctlo~l otop 6 i J, llooctlon rllop 7 i~5 ` OO 3 OH 3 OH 3 (IH) ~IV) (~r) llooctlonr/lop~ (Vl) nonctlon~top 11 / ~~
\ noncl~ol~otop8 ncnotlon alop 9 / \ ~ / llonctlon otop l ~
llonctlon ~tep 1 ~i H~ iO ~ H~
oa 3 ~ . OH 3 J (Vlll) \ nCnCtlo~l 6tCp 17 / (IX) \ncllctlcn 6top 16 ~t / O i /ncactlon 9tep lô \ncDc~ion DtCp 19 M\ ncoctlonotep la nll~3l ~XI3 ¦ ~ \
H ~ ~
"' "' , x, X) \ne~lcliol~otcpzo (Xl) ~ (Xll) 1~ ~/llc~ct~on 3tCp 21 / 14 nln2S~a xe /llcnclion alap az `' I
(Xlll) Ir~c~cLion ahlp 23 - 13 - 2~
And, in the above scheme l, G stands for an optionally substituted hydrocarbon group or an optionally substituted acyl group; Y stands for halogen; Y' stands for halogen excepting chloride; Z
stands for NRIR2 or SRl; L stands for (O)RIR2 or S(O)~ R
(wherein ~ denotes l or 2); M stands for N~RIR2R3-X~ or S~RlR2 ~ X~; R~ ~ R3 and X~ are of the same meaning as defined for those in the general formula (I); provided that when Y is chlorine, G stands for an optionally substituted hydrocarbon group or an optionally substituted acyl group excepting dinitrobenzoyl.
A compound (I), wherein the manner of linkage of the cyclohexane ring with B is ~-type, B is NR4 and D
is 2-methyl-l-isopropenyl, can be produced as the intermediates or the end products shown by (XIX) ~ (XX) to be obtained by conducting the reaction shown by the following scheme 2.
(Scheme 2) llonction stcp 2~ J" nenction step 21; nnaction step 30 'OM OMe ii 'OMe i OMe n~NH 1~4N-G
rum~gillol (Il) tXlV) (XVII) (XVIII) ¦ neaction step 26 ¦neaction step 27 ~ neaction step 31 ~ ¦neaction sLep 33 'OM ~ ' c o tep 29 j :OMe ne~tion ~L~p 33 j OMn (XV) (XVl) n~NH I~IN-G
(XIX) (XX) 2 ~ 2 ~ 3 ~ jJ
And, in the above scheme 2, A and R4 are of the same meaning as those in the general formula (I); and G
is of the same meaning as defined for G in the scheme 1.
S A compound (I), wherein the manner of linkage of the cyclohexane ring with B is a-type, B is O and D is 2-methyl~l-isopropenyl, can be produced as the intermediates or the end products (XXIII) ~ (XXIV) to be obtained by the reaction shown by the scheme 3.
(Scheme 3) ~ ~ ~ ' ~$ l~onction Dtrp 3'i y, ncnction Dtep 36 's, OH ` OMo O a 'Obio rumngillol (Il) (XXI) (XXII) llcnction ntop 39 noactlon atoli 38 noaction Dtop 26 A~ r A
HO~ HO~
Compound(XV)nonctionAlep3~ oaotionrJtop:17 ~
`"OM ~ j OM
(XXIII) (XXIV) And, in the above scheme 3, A is of the same meaning as defined for ~ in the general fo.rmula (I), and G is of the same meanlng as defined for G in khe scheme 1.
A compound (I), wherein the manner of linkage of the cyclohexane ring with r3 is ~-type, B is NR4 and D
is 2-methyl-1-isopropenyl, can be produced as the intermediates or the end products (XXIX) ~ (XXXII) to be obtained by the reaction shown by the scheme 4.
. -( Scheme 4 ) O l~enctioll ~tol) 26 Colllpo~ V) Ol~!lo r~"nn~il10l (Il) \lcncLiol~ slo ~ llonctloll ntol) '10 '\'( (XXV) (xXlx) ~tion sLeD 46 ll nctio= slep 4~/ \
nonctionstoD43 ~~ \ noectlon~l~p44 " ---P ~ '0~ ' \
HN-G HN-O
(X~VI) (XXX) n~c~ 4~
Il~NH OMe I~NH OMe (XXVII) (XXXI) ~aclion step 49 ~ oaction steD 60 /~ I \
~ ~1 /~J, HC~
y r~oactlon step o1 ~J55 n~N-G OMe n~N-G OMo (XXVIII) (XXXII) ~ 3 And, in the above sch0me ~, A is o the same mean.ing as defined for A ln the general formula (I), G
ls of the same meaning as defined for G in the scheme 1 and Rs is an optlonally substituted lower alkyl or aryl group.
~ compouncl (I), wherein D is isobutyl, can be produced by conducting catalytic reduction at an app.ropriate stage in the above-mentioned schema 1~4.
As th~ catalytic reduction, for example a method similar to the catalytic reduction of fumagillol by Tarbell et al. [Tarbell, D. S. et al., J. Am. Chem.
Soc., 83, 3096 (1961)] can be employed.
The reactions shown in the above schema 1 to 4 are individually described in more detail.
~eaction step 1: Production of the compound (III) from fumagillol (II) The compound (III) can be produced by subjecting fumagillol (II) to alkylation, acylation, carbamoylation, thiocarbamoylation, sulfonylation or hydroxycarbamoylation.
Detail description on the alkylation, acylation, carbamoylation, thiocarbamoylation, sulfonylation and hydroxycarbamoylation will be given as follows.
1) Alkylation ~5 This alkylation is conducted by allowing fumagillol to react with an alkylating agent such as alkyl halide (e.g. methyl iodide, ethyl iodid j benzyl bromide, allyl bromide, propargyl bromide, etc.), dialkyl sulfate (dimethyl sulfate, diethyl sulfate, etc.), etc.
This alkylating agent is employed in an amount of usually about 1 to 5 times as much mol. relative to 1 mol. of fumagillol.
This reaction is conducted usually in the presence of a base. As the base, use is made of alkali metal hydrogencarbonates (e.g. sodium hydrogencarbonate, ` ` 2 ~ 3 potassium hydrogencarbonate, etc.), alkali metal carbonates (e.g. sodium carbonate, potassium carbonate, etc.), alkali metal hydrides (e.g. sodium hydride, potassium hydride, etc.), or organic metals (e.g. butyl likhium, lithium di.i.sopropylamide, etc.). The amount o~ the base to be added ranges usually ~rom about 1 to about 5 times as much mol. relative to 1 mol. of fumagillol.
This reaction is carried out usually in an organic solvent which does not exert undesirable influence on the reaction. Examples of such organic solvents as above include amides (e.g. dimethylfoxmamide, dimethylacetamide, etc.), halogenated hydrocarbons (e.g. dichloromethane, chloroform, 1,2-dichloroethane, lS etc.), ethers (e.g. diethyl ether, tetrahydrofuran, dioxane, etc.), esters (e.g. methyl acetate, e-thyl acetate, isobutyl acetate, methyl propionate, etc.), nitriles (e.g. acetonitrile, propionitrile, etc.), nitro compounds (e.g. nitromethane, nitroethane, etc.), ketones (e.g. acetone, methyl ethyl ketone, etc.), aromatic hydrocarbons (e.g. benzene, toluene, etc.), aliphatic saturated hydrogencarbonates (e.g. pentane, hexaner cyclohexane, etc.), etc., and these solvents may be used singly or as a mixture of two or more species of them in a suitable ratio.
Whila the reaction temperature varies with the amounts, kinds, etc. of alkylating agents, bases and solvents, it ranges from -80C to 100C, preferably from 0C to 80C. The reaction time ranges from about 20 minutes to about 5 days.
2) Acylation This acylation i5 conducted by allowing a ~eactive derivative of activated carboxylic acid, such as acid anhydride, acid halide, activated amide, activated ester, activated thioester, etc. to react with fumagillol.
These reactive derivatives are specifically described as follows.
i) Acid halide :
For example, acid chlorlde, acid bromide, etc. are employed.
ii) Acid anhydride :
For example, symmetric acid anhydrides, mixed acid anhydrides with a lower alkyl carbonate, etc. are employed.
iii) Active amide :
For example, amides with pyrazole, imidazole, 4-substituted imidazole, dimethyl pyrazole, benzotriazole, etc. are employed.
iv) Active ester :
For example, besides esters such as methoxymethyl ester, benzotriazole ester, 4-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, etc., are employed esters with 1-hydroxy~lH-2-pyridone, N-hydxoxysuccinimide, N-hydroxyphthalimide, etc.
v) Active thioester :
For example, thioesters with heterocyclic thiol such as 2-pyridyl thiol, 2-benzothiazolyl thiol, etc.
are employed.
A reaction derivative of the carboxylic acid is employed in an amount of usually about 1 to 10 times as much mol., preferably 1 to 5 times as much mol., relative to 1 mol. of fumagillol. And, in case of using the carboxylic acid as its free state, the reaction is conducted preerably in the p.resence of a condensing agent. As the condensing agent, use is made of, for example, N,N~-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N
cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide, N-ethyl-N'-t3-dimethylaminopropyl)carbodiimide, diphenylphospholylazide, diethyl cyanophosphate, etc.
, 2 ~
This reaction is carried out usually in the presence of a base. As the base, use is made of the bases mentioned in the description of the alkylation, and the amount to be added ranges from about 1 mol. to 10 times as much mol. relative to 1 mol. of fumagillol.
This reaction is carried out usually in an organic solvent which does not e~ert undesirable influence on the reaction. As such organic solvents, use is made of those mentioned in the description of the alkylation.
The reaction temperature varies with the amount, kinds, etc. of carboxyli.c acid derivatives, bases and solvents, but it ranges from -~0C to 100C, preferably from 0C to 80C. The reaction time ranges from about 30 minutes to about 5 days.
lS 3) Carbamoylation :
Carbamoylation for introducing a mono-substituted carbamoyl group is carried out by usually allowing isocyanate to react with fumagillol.
This isocyanate is used in an amount of usually about 1 mol. to about 5 times as much mol. relative to 1 mol. of fumagillol This reaction may be conducted in the presence of a base. As the base, use is made of bases mentioned in the description of the alkylation in an amount ranging 25` from about 1 mol. to 10 times as much mol. relative to 1 mol. of fumagillol.
This reaction is carried out usually in an organic solvent which does not exert undesirable influence on the reaction. As such organic solvents as above, use is made of those mentioned in the description of the alkylation.
The reaction temperature varies with the amounts and kinds of isocyanate, the base and the solvent then employed, and it usually ranges from about -80C to 100C, preferably from 0C to 80C. The reaction time ranges from about one hour to about five days.
2 ~
Among the compounds having mono-substituted carbamoyl group thus obtained, compounds having, for example, chloroacetyl carbamoyl, trichloroacetyl carbamoyl, etc., can be converted t.o compounds having S carbamoyl c3roup by removing chloroacetyl group or trichloroacetyl group by a conventional process (e.g.
at room temperatures or elevated ~emperatures und0r basic conditions).
~lhe said carbamoylation can also be conducted by allowing fumagillol to react with carbamoyl halide.
The said carbamoyl halide is used in an amount usually ranging from l mol. to 5 times as much mol.
relative to 1 mol. of fumagillol.
This reaction is carried out usually in the presence of a base. As the base, use is made of bases mentioned in the description of the alkylation, and the amount of the base to be added ranges usually from about 1 mol. to about lO times as much mol. relative to 1 mol. of fumagillol.
This reaction is carried out usually in an organic solvent which does not exert undesirable influence on the reaction. Examples of such organic solvents as abo~e include those mentioned in the description of the alkylation.
The reaction temperature vary with the amounts and kinds of carbamoyl halide, bases and solvents, and it ranges from about 0C to around the reflux temperature of the reaction medium, preferably from about 25C to reflux temperature.
The said carbamoylation can also be carried out by allowing the 1,1-carbonyldiimidazole to react with the fumagillol to give an active ester, followed by allowing the ester to react with ammonia, primary amines (e.g. methylamine, ethylamine, isopropylamine, etc.), or secondary amine (e.g. dimethylamine, ; ethylmethylamine, dimethylamine, pyrrolidine, 2~1k3 piperidine, N-methylpiperazine, morpholine, etc.).
1,1-Carbonyldilmidazole, ammonia, primary amines and secondary amines are employed in an amount ranging from usually 1 mol. to 5 times as much mol. relative to S 1 mol. of fumagillol.
This reaction is carried out usually in an organic solvent which does not exert undesirable influence. As such organic solvents, use is made of those mentioned in the description of the alkylation.
While the reaction temperature varies with the amounts and kinds of ammonia, primary amines, secondary amines and solvents, it ranges from -20C to the reflux temperature o~ the reaction medium, preferably from 0C
to 50C. The reaction time ranges from 20 minutes to about 5 days.
Incidentally, the active esters obtained as intermediates are included in the category of the compound (III).
Among the compound ~III) wherein G is a mono-substituted carbamoyl group, a compound (III) wherein is a substituted lower alkanoyl carbamoyl group can also be prepared by allowing a compound (III) wherein G
is chloroacetyl carbamoyl to react with a nucleophilic reagent.
As the nucleophilic reagent, use is made of a lower carboxylic acid, a lower thiocarboxylic acid, thiols, amines and metal salts of them, and the amount of such reagent ranges usually from about 1 mol. to about 20 times as much mol. relative to 1 mol. of the starting compound, preferably from 1 mol. to 5 times as much mol.
This reaction is conducted usually in the presence of a base. As the base, use is made of those mentioned in the description of the alkylation, and its amount to be added ranges usually from about 1 mol. to 10 times as much mol. relative to 1 mol. of the starting - 23 - ~ ~2 compound.
This reaction is usually carried out in an organic solvent which does not exert undesirable i.nfluence on the reaction. As the organic solvents exertin~ rlo undesirable in1uence on ~he reaction, use is made of those mentioned in the clescription of the alkylation.
While the reaction temperature varies with the amounts, kinds, etc. o the nucleophilic reagents, bases and solvents, it ranges usually from -80C to lOO~C, preferably from 0C to 80C. The reaction time ranges from about 20 minutes to 5 days.
4) Thiocarbamoylation In the above-mentioned carbamoylation~ by conducting similar reaction employing thioisocyanate in place o~ isocyanate, a derivative into which mono--substituted thiocarbamoyl group is introduced can be synthesi.zed.
This invention relates to novel cyclohexanol derivatives and their use.
BACRGROUND TECHNOLOGY
Angiogenesis is deeply concerned with occurrence of pathological processes o~ various in1ammatory diseases (rheumati.c diseases, psoriasis, etc.), diabetic retinopathy, tumors, etc. Therefore, it has been considered that inhibition of angiogenesis has a connection with therapy and prophylaxis of these diseases and several groups have searched for substances capable of inhibiting angiogenesis. For example, mention is made of research works for application of Protamine by Taylor [Taylor, S, et al., Nature, 297, 307 (1982)] and for use of heparin in the presence of cortisone by Folkman et al. [Folkman, J. et al., Science, 221, 719 (1983)]. Furthermore, patent applications have been filed directed to ascorbic acid ether and its re].ated compounds (JP-A-131978/1983) or polysaccharide sulfate DS4125 (JP-~-119500/1988) as compounds showing activity of inhibiting angiogenesis.
However, the activities of these compounds are not sufficiently satisfactory, and compounds having more satisfactory activity are desired.
OBJECT OF THE INVENTION
The object of the present invention lies in providing novel compounds having an action of inhibiting angiogenesis and an anti-tumor action, whose toxicity to hosts is low.
To attain the above-mentioned object, the present inventors have conducted searches for various compounds and evaluation of them. As a result, they found that cyclohexanol derivatives, chemically derived from fumagillol, hydrolysate of fumagillin which has been 2 ~
known as an antibiotic agent and an antiprotozoal agent, have a superb action of inhibiting angiogenesis and an anti-tumor action, and that they are less Loxic to hosts, thus the present invention has been accomplished.
SUMMARY_OF ~HE INVENTION
More specifically, the present invention i9 to provide A compound represented by the formula:
HO~CH2D
~"1"~
I Ol~e B--E
wherein A i.s halogen, N(O)mR~R2, N~RlR2R~ X~, S(O)nR~ or S~(O)mRlR2-X~ (where Rl,R2 and R3 are each optionally substituted hydrocarbon group or heterocyclic group, X~
is a counter anion; m is an integer of~0 or 1; n is an integer of 0 to 2; Rl and R2 may form a nitrogen-containing or a sulfur-containing heterocyclic ring, which may further form a condensed ring, with the `adjacent nitrogen atom or sulfur atom, and these nitrogen-containing or sulfur-containing heterocyclic rings may have substituents); B is O or NR4 (where R4 is hydrogen or an optionally substituted lower alkyl or aryl group); D is 2-methyl-1-propenyl group or isobutyl group; and E is hydrogen, an optionally substituted hydrocarbon group or an optionally substituted acyl group; provided that, when A is chlorine, E is an optionally substituted hydrocarbon group or acyl ~ excepting dinitrobenzoyl, or a sàlt thereof, its production, and an antitumor agent containing a compound represented by the formula:
2 ~
NO C~l a C}J 2 D
f~/
~O~le (I') B--E' wherein A is halogen, N(O)mR~R2, N~RIR2R3-X~, S(O)nR~ or S~(O)mRIR2~X~ (where Rl,R2 and R3 are each optionally substituted hydrocarbon group or heterocyclic group, X~
is a counter anion; m is an integer of 0 or 1; n is an integer of 0 to 2; Rl and R2 may form a nitrogen-containing or a sul~ur-containing heterocyclic ring, which may further form a condensed ring, with the adjacent nitrogen atom or sulfur atom, and these nitrogen-containing or sulfur-containing heterocyclic rings may have substituents); B is O or NR4 (where R4 is hydrogen or an optionally substituted lower alkyl or aryl group); D is 2-methyl~1-propenyl group or isobutyl group; and E' is hydrogen, an optionally substituted hydrocarbon group or an optionalIy substituted acyl group, or a salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
In the above-mentioned formulae (I) and (I'), the halogen shown by A includes fluorine, chloriner bromine and iodine.
Examples of the hydrocarbon groups of the - optionally substituted hydrocarbon groups shown ~y Rl, R2 or R3 include straight-chained or branched Cl6 alkyl groups (e.g. methyl, ethyl, propyl, isopropylj butyl, isobutyl, sec-butyl, pentyl, isopentyl, hexyl, etc.), C2-6 alkenyl groups (e.g. vinyl, allyl, 2-butenyl, methylallyl, 3-butenyl, 2-pentenyl~ 4-pentenyl, 5-hexenyl, etc.), C26 alkynyl groups (e.g. ethynyl, propargyl, 2-butyn-l-yl, 3-butyn2-yl, 1-pentyn-3-yl, 3-:
- 4 - 2~
pentyn-].-yl, 4-pentyn-2-yl, 3-hexyn-1-yl, etc.), C36 cycloalkyl groups (e.~. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), C~6 cycloalkenyl groups (e.g. cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, etc.), C71~ aralkyl g~oups (e~g.
benxyl, l-phenethyl, 2-phenethyl, etc.), and C6~0 aryl groups (e.g. phenyl, naphthyl, etc.).
Examples of the heterocyclic groups of the optionally substituted heterocyclic groups shown by Rl, R2 or R3 include 5- or 6-membered heterocyclic groups containing 1 to 4 hetero-atoms such as nitrogen, oxygen, sulfur, etc. (e.g. 2-furyl, 2-thienyl, 4-thiazolyl, 4~imidazolyl, 4-pyridyl, 1,3,4-thiadiazol-2 yl, 1-methyl-5-tetrazolyl, etc.). These heterocyclic groups may form bicyclic condensed rings by condensation with 5- or 6-membered ring such as benzene, pyridine, cyclohexane, etc. (e.g. 8-quinolyl, 8-purinyl, etc.) Examples of the nitrogen-containing heterocyclic groups which may be formed by Rl and R2 together with the adjacent nitrogen atom include 4- to 7-membered nitrogen-containing he-terocyclic groups (e.g.
pyrrolidin-l-yl, piperazino, morpholino, 4-methylpiperazin-1-yl, etc.).
Examples of the sulfur-containing heterocyclic groups which may be formed by Rl and R2 together with the adjacent sulfur atom include 4- to 7-membered - sulfur containing heterocyclic groups (e.g.
tetrahydrathiophen-1-yl, 1,4-thioxan-l-yl~ etc.).
The nitrogen-containing or sulfur-containing heterocyclic groups which may be formed by Rl and R2 together with the adjacent nitrogen atom or sulfur atom may be condensed with a 5- or 6-membered cyclic group (e.g. benzene, pyridine, pyrazine, pyridazine, cyclohexane, cyclohexene, etc.) to form bicyclic condensed rings (e.g. isoindolin-2-yl, 2-isoquinolyl, 2 ~ 2 '~
1,3-dihydrobenzo[c]thiophen-2-yl, 2,3-dihydrobenzo[b]thiophen-1-yl, 1,3,3a,4,7,7a-hexahydrobenzo[c]thiophen-2-yl, perhydrobenzo[c]th.iophen 2-yl, 3,4-dihydro-lH-2-benzopyran-2-yl, 3,4-dihydro-2H-l-benzopyran-1-yl, 1,2,~,5-tetrahydro-3-benzothiepin-3~yl t 1,3-dihydrothieno[3,4-c]pyridin-2-yl, S,7-dihydrothieno[3,4-b]pyrazin-6-yl, 5,7-dihydrothieno[3,4-d]pyridazin-6-yl, etc.) Examples of the lower alkyl groups of the optionally substituted lower alkyl groups shown by R4 include Cl6 alkyl groups (e.g. methyl, ethyl, propyl, isopropyl, butyl, is~butyl, sec-butyl, pentyl, isopentyl, hexyl, etc.).
As the aryl groups of the optionally substituted aryl groups shown by R4, mention is made of C6~10 aryl groups (e.g. phenyl, naphthyl, etc.).
As the optionally substituted hydrocarbon groups shown by E or E', mention is made of those specifically described above as the optionally substituted hydrocarbon groups shown by Rl, R2 and R3.
As the optionally substituted acyl groups shown by E or E', mention is made of the residues of acids such as carboxylic acid acyl, sulfonic acid acyl, carbamoyl, thiocarbamoyl, sulfamoyl, etc., and examples of them include respectively optionally substituted alkanoyl, aroyl, heterocyclic carbonyl, carbamoyl, thiocarbamoyl, arylsulfonyl, alkylsulfonyl, sulfamoyl, alkoxycarbonyl, aryloxycarbonyl, etc.
As the alkanoyl groups of the above-mentioned optionally substîtuted alkanoyl groups, mention is made of Cl10 alkanoyl groups (e.g. formyl, acetyl, propionyl, isopropionyl, butyryl, pentanoyl, hexanoyl, etc.).
As the aroyl groups of the optionally substituted aroyl groups, mention is made of C7l0 aroyl groups - 6 - 2~2~t~
(e.g. benzoyl, 1-naphthoyl, 2-naphthoyl, etc.).
As the heterocyclic carbonyl groups in the optionally substituted heterocyclic carbonyl groups, mention is made of 5- or 6-membered heterocyclic carbonyl groups containing 1 to 4 hetero-atoms such as nitrogen, oxygen, sulfur, etc. (e.g. ~-~uroyl, 2-thenoyl, nicotinoyl, isonicotinoyl, etc.).
As the arylsulfonyl groups of the optionally substituted arylsulfonyl groups, mention is made of C6 lo arylsulfonyl groups (e.g. benzenesul~onyl, 2-naphthylsulfonyl, etc.).
As the alkylsulfonyl groups of the optionally substituted alkylsulfonyl groups, mention is made of Cl6 alkylsulfonyl groups te.g. methylsulfonyl, ethylsulfonyl, etc.).
As the alkoxycarbonyl groups of the optionally substituted alkoxycarbonyl groups, mention is made of C27 alkoxycarbonyl groups (e.g. methoxycarbonyl, ethoxycarbonyl, isobutoxycarbonyl, etc.).
As the aryloxycarbonyl groups of the optionally substituted aryloxycarbonyl groups, mention is made of C7il aryloxycarbonyl groups (e.g. pheno~ycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl, etc.
The respectively optionally substituted hydrocarbon groups or hetarocyclic groups shown by Rl, R2 or R3, the nitrogen-containing or sulfur-containing - heterocyclic groups which may be ~ormed by Rl and R2 together with the adjacent nitrogen atom or sulfur atom and may form condensed ring, the respectively optionally substituted lower alkyl groups or aryl groups shown by R4, and the respectively optionally substituted hydrocarbon groups or acyl groups (e.g.
alkanoyl group, aroyl group, heterocyclic carbonyl group, carbamoyl group, thiocarbamoyl group, arylsulfonyl group, alkylsulfonyl group, sulfamoyl group, alkoxycarbonyl group or aryloxycarbonyl group) - 7 - 2 ~ t~
shown by E or E' may have 1 to 3 substituents at any posi.tions possibly substituted.
Examples of these substituents include Cl6 alkyl groups (e.g. methyl, ethyl, propyl, isopxopyl, butyl, sec-butyl, pentyl, isopentyl, hexyl, etc.), C26 alkenyl groups te.g. vi.nyl, allyl, 2-butenyl, methylallyl, 3-butenyl, 2-pentenyl, 4-pentenyl, S-hexenyl, etc.), C26 alkynyl groups (e.g. ethynyl, propargyl, 2-butyn-1-yl, 3-butyn-2-yl, 1-pentyn-3-yl, 3-pentyn-1-yl, 4-pentyn-2-yl, 3-hexyn-1-yl, etc.), C36 cycloalkyl groups (cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), C36 cycloalkenyl groups (e.g. cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, etc.), C6l0 aryl groups (e.g. phenyl, naphthyl, etc.), amino, Cl6 alkylamino groups (e.g. methylamino, ethylamino, isopropylamino, etc.), diCI6 alkylamino groups (e.g.
dimethylamino, diethylamino, etc.), azido, nitro, halogen (e.g. fluorine, chlorine, bromine, iodine, etc.)~ hydroxyl, Cl4 alkoxy groups (e.g. methoxy, ethoxy, etc.), C6l0 aryloxy groups (e.g. phenoxy, naphthyloxy, etc.), Cl6 alkylthio groups (e.g.
methylthio, ethylthio, propylthio, etc.), C6l0 arylthio groups (e.g. phenylthio, naphthylthio, etc.), cyano, carbamoyl groups, carboxyl groups, C14 alkoxycarbonyl groups (e.g. methoxycarbonyl, ethoxycarbonyl, etc.), C7ll aryloxycarbonyl groups (e.g. phenoxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl, etc.), carboxy Cl4 alkoxy groups (e.g. carboxymethoxy, 2-carboxyethoxy, etc.~, C16 alkanoyl groups (e.g. formyl, acetyl, propionyl, isopropionyl, butyryl, pentanoyl, hexanoyl, etc.), C7l1 aroyl groups (e.g. benzoyl, 1-naphthoyl, 2-naphthoyl, etc.), C6l0 arylsulfonyl groups (e.g. benzenesulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, etc.), Cl6 alkylsulfinyl groups (e.g.
methylsulfinyl, ethylsulfinyl, etc.), C6l0 arylsulfinyl groups (e.g. benzenesulfinyl, 1-naphthylsulfinyl, 2-- 8 - 2~
naphthylsulfinyl, etc.), Cl6 alkylsulfonyl groups (e.g.
methylsulfonyl, ethylsulfonyl, etc.), 5- or 6-membered heterocycllc groups containing 1-4 hetero~atoms such as nitrogen, oxygen, sulfur, etc. (e.g. 2-furyl, 2-S thienyl, ~-thiazolyl, 4-imidazolyl, 4-pyridyl, l,3,4-thiadiazol-2-yl, 1-methyl-5-tetrazolyl, etc.), 5- or 6-membered heterocyclic carbonyl groups containing 1 to 4 hetero-atoms such as nitrogen, oxygen, sulfur, etc.
(e.g. 2-furoyl, 2-thenoyl, n:icotinyl, isonicotinyl, etc.), and 5- or 6-membered heterocyclic groups containing 1 to 4 hetero-atoms such as nitrogen, oxygen, sulfur, etc., (e.g. 4-pyridylthio, 2-pyrimidylthio, 1,3,4-thiadiazol-2-ylthio, l-methyl-5-tetrazolylthio, etc.) and the heterocyclic thio groups lS may be fused with benzene ring to form bicyclic condensed ring thio groups (e.g. 2-benzothiazolylthio, 8-quinolylthio, etc.). And, when ~ or E~ each stands for di-substituted carbamoyl group, thiocarbamoyl group or sulfamoyl group, it may form, taken together with the nitrogen atom of the carbamoyl group, thiocarbamoyl group or sulfamoyl group, a nitrogen-containing heterocyclic group (e.g. pyrrolidin-1-yl, piperidino, morpholino, piperazin-l-yl, 4-methylpiperazin-1-yl, 4-phenylpiperazin-yl, etc.
And, the substituants in the respectively optionally substituted hydrocarbon groups or heterocyclic groups shown by Rl, R2 or R3, the substituents in the nitrogen-containing or sulfur-containing heterocyclic groups, which may be formed by Rl and R2 together with adjacent nitrogen atom or sulfur atom, which may further form condensed ring, the substituents in the respectively optionally substituted lower alkyl groups or aryl groups shown by R4, and the substituents in the respectively optionally substituted hydrocarbon groups, alkanoyl groups, aroyl groups, heterocyclic carbonyl groups, carbamoyl groups, 2~3g~;
thiocarbamoyl groups, aryl sulfonyl groups, alkyl sulfonyl groups, sulfamoyl groups, alkoxy carbonyl ~roups or aryloxy carbonyl groups, which are shown by E
or E', may further have 1 to 3 substituents at subst.i.tutive positions.
As these substituents, use is made of those as exemplifi.ed by the substituents in the respectively optionally substituted hydrocarbon groups or heterocyclic groups shown by Rl, R2 or R3, the substituents in the nitrogen-containing or sulfur-containing heterocyclic groups, which may be formed by Rl and R2 together with adjacent nitrogen atom or sulfur atom, which may further form condensed ring, the substituents in the respectively optionally substituted lower alkyl groups or aryl groups shown by R4, and the substituents in the respectively optionally substituted hydrocarbon groups, alkanoyl groups, aroyl groups, heterocyclic oarbonyl groups, carbamoyl groups, thiocarbamoyl groups, aryl sulfonyl groups, alkyl sulfonyl groups, sulfamoyl groups, alkoxy carbonyl groups or aryloxy carbonyl groups, which are shown by E
or E', as they are.
Examples of the counter anion shown by X~ include halogen ion (e.g. iodide ion, bromide ion, chloride ion, etc.), sulfate ion, phosphate ion, nitrate ion, perchlorate ion, tetrafluoroborate ion, methanesulfonate ion, p-tolylsulfate ion, benzenesl.lfate ion, hydroxyl ion, carboxyl ion of organic acid (oxalate ion, maleate ion, fumarate ion, succinate ion, citrate ion, lactate ion, trifluoroacetate ion, lactobionate ion, acetate ion, propionate ion, tartrate ion, ethyl succinate ion, etc.).
While the compound (I) or (I~) has the asymmetric center in the molecule and has optical acti~ity, its absolute structure is based on fumagillol employed as 2 ~ 2 ~
the starting material. This means that the absolute structure is in agreement with that o fumagillol. In the description of manner o~ linkage of the substituents on the cyclohexane ring, ~'''' shows a-lin~age, ~ show ~-linkage, and shows the ca~e where the linkage may be either ~-type or ~-type.
When the compound o~ this in~ention has, in its molecule, an acid substituent (e.g. carboxyl, etc.) or a basic substituent (e.g. amino, a lower alkylamino, a di-lower alkylamino, a nitrogen-containing heterocyclic group, etc.), it can be used as a physiologically acceptable salt as well. Examples of the physiologically acceptable salt include salts with inorganic bases, salts with organic bases, and salts with basic or acid amino acids. E~amples of inorganic bases include alkali metals (e.g. sodium, potassium, etc.) and alkaline earth metals (e.g. calcium, magnesium, etc.), examples of organic bases include trimethylamine, triethylamine, pyridine, picoline, N,N-dibenzylethylenediamine, ethanolamine, diethanolamine,tris-hydroxymethylaminomethane, dicyclohexylamine, etc., examples of inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., examples of organic acids include formic acid, acetic acid, trifluoroacetic acid, oxalic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and exampIes of basic or acid amino acids include arginine, lysine, ornithine, aspartic acid, glutamic acid, etc. Among these salts, those with bases (i.e. salts with inorganic bases, salts with organic bases, salts with basic amino acids) mean salts which can be formed with the carboxyl group in the substituents of the compound (I) and (I'), and salts with acids (i.e. salts with inorganic acids, salts with organic acids, salts with acid amino acids) g ~ean salts -~hich can oe ~^or~ed with amino group, a lower al.~ l-amino group, di-lower alkylamino group, a nitro~en-contain-~g heterocyclic group, etc. in the substituents of the compound (I).
~ d, when the compound (I) and (I') have intramolecularlv a di-lower alkyl~mino qroup, a nitroyen-containing heterocycl'c group or a nitroyen-containing aromatic heterocyclic group, the nitrogen atom in these suhstituents may rurther be alkylated to form a quaternay ammonio group (e.g. trimethylammonio, N-methyl-pyridinio, N-methylpyrrolidin-L-ylio, etc.), and, as the counter anion, mention is made of counter anion similar to that shown by the afore-mentioned X .
In the compound (I) and (I'), A is preferably N(O)mRlR , N RlR2R3-X , S(O)nRl and S (O)mRlR2- X , especially S RlR X
wherein Rl and R2 are hydrocarbon group and X is halogen.
As B, O or N~ is preferable, as D, 2-methyl-1-propenyl is preferable, and, as E or E', substituted carbamoyl is preferable.
When A is -S RlR X , a particularly preferred value for -S RlR2 is 1,3-dihydrobezo[c~thiophen-2-ylio, tetrahydrothiophen-l -ylio, 1,3,3a,4,7,7a-hexahydrobenzo[c]thiophen-2-ylio, dimethyl-sulfonio, ethylmethylsulfonio, benzylmethylsulfonio, (2-propynyl) methylsulfonio, allylmethylsulfonio, (4-bromobenzyl)methylsulfonio, (4-chlorobenzyl)methylsulfonio, (4-fluorobenzyl)methylsultonio, (4-methylbenzyl)methylsulfonio, (3-bromobenzyl)methylsulfonio, (2-bromobenzyl)methylsulfonio, diallysulfonio or dibenzylsulfonio.
When A is -SR2, -SOR2 or -S02R2, a preferred value for A
is phenylthio, l-naphthylthio, 8-quinolylthio, methylthio, phenyl-sulfinyl, methylsulfinyl, methylsulfonyl, 4-pyridylthio, ~-methyl-4-pyridiniothio, 2-pyrimidinylthio, ethylthio, allylthio, 2~ 3~
- :~- 2'~ -3a 2-hydro~benzylthio, 2-me-hanesulfonylcxybenzylth-o, 4-hyd-oxybu.-~-lflthio, ~-methanesulfonyloxybutyrylthio, 2-chloromethylbenzilth~o, 2-hvdroxyethylthio, 4-chlorobenzylthio, 4-bromobenzylthio, ~-flu-orobenzylthio, 4-methylbenzylthio, 3-bromobenzylthio, 2- bn~x~
benzylthio, 3,4,5,6-tetrafl~oro-2-hydroxymethylbenzylthio, 3,~,5,6-tetrafluoro-2-methanesulfonyloxybenzylthio or 6-hydroxymethyl-3-cyclohexenylmethylthio~
A class of compounds within the scope of the formula (I) are those in which: B is O and E is hydrogen, C1 l~alkanoyl, C7 10aroyl, C2 7alkoxycarbonyl, Cl 6alkylsulfonyl, C7_11aryloxy-carbonyl or carbamoyl which may be ~ubstituted by C3 6alkenyl, Cl_6alkyl, or C6 1Oaryl, Cl 6alkanoyl ~which may further be substituted by halogen, Cl_6alkylthio, C7_11aralkylthio, C6_10aryl-thio, benzothiazolylthio or quinolylthio).
A particularly preferred group for the substituted carbamoyl group includescarbamoyl, chloroacetylcarbamoyl, acryloyl-carbamoyl, methacryloxylcarbamoyl, 3-chloro-2-methylpropionyl-carbamoyl, phenylthioacetylcarbamoyl, 1-naphthylthioacetylcarba-moyl, 8-quinolylthioacetylcarbamoyl, l-naphthylcarbamoyl, 2-benzothiazolylthioacetylcarbamoyl, morpholinocarbonyl, chloro-methylcarbamayl, 2-chloroethylcarbamoyl, (2~benzothiazolylthio) thioacetylcarbamoyl, methylthioacetylcarbamoyl and benzylth o-acetylcarbamoyl.
Another class of compounds within the scope of the formula (I) are those in which: B is -NH, and ~ is the acyl. A particu-larly preferred acyl for E in this group is the carbamoyl mentioned above. An especially preferred group for -B-E in this class is N chloroacetylureido.
~ 3 ~
llb 24205-885 The compound of this invention represented by the general formula (I) can be produced by employing, as the starting material, fumagillol, which is the hydrolysate of fumagillin produced by microorganism, [Tarbell, D. S. et al., ~J. Am. Chem. Soc.) 83, 3096 (1961)]. The production method is described in detail as follows.
A compound (I), wherein the manner of linkage of the cyclohexane ring with B is ~-type, B is O and D is 2-methyl-1-isopropenyl, can be produced as the intermediates or the end products shown by (IV) ~ (XIII) to be obtained by conducting the reaction shown by the following scheme 1.
-- 12 -- 2 ~ 2 ~
(Scheme ].) ~J `~
OH OCH ~ \
llonclionhtopl / iulllnillllol(ll) \ Itonclln~Rtop~i Itoncllo-~ nlop 3 \~
~/llonclin~ Rl~p7 Y~ y~ Z~
H ~ ~ H9~
J. llonclioll ololl 5 i~i nonctlo~l otop 6 i J, llooctlon rllop 7 i~5 ` OO 3 OH 3 OH 3 (IH) ~IV) (~r) llooctlonr/lop~ (Vl) nonctlon~top 11 / ~~
\ noncl~ol~otop8 ncnotlon alop 9 / \ ~ / llonctlon otop l ~
llonctlon ~tep 1 ~i H~ iO ~ H~
oa 3 ~ . OH 3 J (Vlll) \ nCnCtlo~l 6tCp 17 / (IX) \ncllctlcn 6top 16 ~t / O i /ncactlon 9tep lô \ncDc~ion DtCp 19 M\ ncoctlonotep la nll~3l ~XI3 ¦ ~ \
H ~ ~
"' "' , x, X) \ne~lcliol~otcpzo (Xl) ~ (Xll) 1~ ~/llc~ct~on 3tCp 21 / 14 nln2S~a xe /llcnclion alap az `' I
(Xlll) Ir~c~cLion ahlp 23 - 13 - 2~
And, in the above scheme l, G stands for an optionally substituted hydrocarbon group or an optionally substituted acyl group; Y stands for halogen; Y' stands for halogen excepting chloride; Z
stands for NRIR2 or SRl; L stands for (O)RIR2 or S(O)~ R
(wherein ~ denotes l or 2); M stands for N~RIR2R3-X~ or S~RlR2 ~ X~; R~ ~ R3 and X~ are of the same meaning as defined for those in the general formula (I); provided that when Y is chlorine, G stands for an optionally substituted hydrocarbon group or an optionally substituted acyl group excepting dinitrobenzoyl.
A compound (I), wherein the manner of linkage of the cyclohexane ring with B is ~-type, B is NR4 and D
is 2-methyl-l-isopropenyl, can be produced as the intermediates or the end products shown by (XIX) ~ (XX) to be obtained by conducting the reaction shown by the following scheme 2.
(Scheme 2) llonction stcp 2~ J" nenction step 21; nnaction step 30 'OM OMe ii 'OMe i OMe n~NH 1~4N-G
rum~gillol (Il) tXlV) (XVII) (XVIII) ¦ neaction step 26 ¦neaction step 27 ~ neaction step 31 ~ ¦neaction sLep 33 'OM ~ ' c o tep 29 j :OMe ne~tion ~L~p 33 j OMn (XV) (XVl) n~NH I~IN-G
(XIX) (XX) 2 ~ 2 ~ 3 ~ jJ
And, in the above scheme 2, A and R4 are of the same meaning as those in the general formula (I); and G
is of the same meaning as defined for G in the scheme 1.
S A compound (I), wherein the manner of linkage of the cyclohexane ring with B is a-type, B is O and D is 2-methyl~l-isopropenyl, can be produced as the intermediates or the end products (XXIII) ~ (XXIV) to be obtained by the reaction shown by the scheme 3.
(Scheme 3) ~ ~ ~ ' ~$ l~onction Dtrp 3'i y, ncnction Dtep 36 's, OH ` OMo O a 'Obio rumngillol (Il) (XXI) (XXII) llcnction ntop 39 noactlon atoli 38 noaction Dtop 26 A~ r A
HO~ HO~
Compound(XV)nonctionAlep3~ oaotionrJtop:17 ~
`"OM ~ j OM
(XXIII) (XXIV) And, in the above scheme 3, A is of the same meaning as defined for ~ in the general fo.rmula (I), and G is of the same meanlng as defined for G in khe scheme 1.
A compound (I), wherein the manner of linkage of the cyclohexane ring with r3 is ~-type, B is NR4 and D
is 2-methyl-1-isopropenyl, can be produced as the intermediates or the end products (XXIX) ~ (XXXII) to be obtained by the reaction shown by the scheme 4.
. -( Scheme 4 ) O l~enctioll ~tol) 26 Colllpo~ V) Ol~!lo r~"nn~il10l (Il) \lcncLiol~ slo ~ llonctloll ntol) '10 '\'( (XXV) (xXlx) ~tion sLeD 46 ll nctio= slep 4~/ \
nonctionstoD43 ~~ \ noectlon~l~p44 " ---P ~ '0~ ' \
HN-G HN-O
(X~VI) (XXX) n~c~ 4~
Il~NH OMe I~NH OMe (XXVII) (XXXI) ~aclion step 49 ~ oaction steD 60 /~ I \
~ ~1 /~J, HC~
y r~oactlon step o1 ~J55 n~N-G OMe n~N-G OMo (XXVIII) (XXXII) ~ 3 And, in the above sch0me ~, A is o the same mean.ing as defined for A ln the general formula (I), G
ls of the same meaning as defined for G in the scheme 1 and Rs is an optlonally substituted lower alkyl or aryl group.
~ compouncl (I), wherein D is isobutyl, can be produced by conducting catalytic reduction at an app.ropriate stage in the above-mentioned schema 1~4.
As th~ catalytic reduction, for example a method similar to the catalytic reduction of fumagillol by Tarbell et al. [Tarbell, D. S. et al., J. Am. Chem.
Soc., 83, 3096 (1961)] can be employed.
The reactions shown in the above schema 1 to 4 are individually described in more detail.
~eaction step 1: Production of the compound (III) from fumagillol (II) The compound (III) can be produced by subjecting fumagillol (II) to alkylation, acylation, carbamoylation, thiocarbamoylation, sulfonylation or hydroxycarbamoylation.
Detail description on the alkylation, acylation, carbamoylation, thiocarbamoylation, sulfonylation and hydroxycarbamoylation will be given as follows.
1) Alkylation ~5 This alkylation is conducted by allowing fumagillol to react with an alkylating agent such as alkyl halide (e.g. methyl iodide, ethyl iodid j benzyl bromide, allyl bromide, propargyl bromide, etc.), dialkyl sulfate (dimethyl sulfate, diethyl sulfate, etc.), etc.
This alkylating agent is employed in an amount of usually about 1 to 5 times as much mol. relative to 1 mol. of fumagillol.
This reaction is conducted usually in the presence of a base. As the base, use is made of alkali metal hydrogencarbonates (e.g. sodium hydrogencarbonate, ` ` 2 ~ 3 potassium hydrogencarbonate, etc.), alkali metal carbonates (e.g. sodium carbonate, potassium carbonate, etc.), alkali metal hydrides (e.g. sodium hydride, potassium hydride, etc.), or organic metals (e.g. butyl likhium, lithium di.i.sopropylamide, etc.). The amount o~ the base to be added ranges usually ~rom about 1 to about 5 times as much mol. relative to 1 mol. of fumagillol.
This reaction is carried out usually in an organic solvent which does not exert undesirable influence on the reaction. Examples of such organic solvents as above include amides (e.g. dimethylfoxmamide, dimethylacetamide, etc.), halogenated hydrocarbons (e.g. dichloromethane, chloroform, 1,2-dichloroethane, lS etc.), ethers (e.g. diethyl ether, tetrahydrofuran, dioxane, etc.), esters (e.g. methyl acetate, e-thyl acetate, isobutyl acetate, methyl propionate, etc.), nitriles (e.g. acetonitrile, propionitrile, etc.), nitro compounds (e.g. nitromethane, nitroethane, etc.), ketones (e.g. acetone, methyl ethyl ketone, etc.), aromatic hydrocarbons (e.g. benzene, toluene, etc.), aliphatic saturated hydrogencarbonates (e.g. pentane, hexaner cyclohexane, etc.), etc., and these solvents may be used singly or as a mixture of two or more species of them in a suitable ratio.
Whila the reaction temperature varies with the amounts, kinds, etc. of alkylating agents, bases and solvents, it ranges from -80C to 100C, preferably from 0C to 80C. The reaction time ranges from about 20 minutes to about 5 days.
2) Acylation This acylation i5 conducted by allowing a ~eactive derivative of activated carboxylic acid, such as acid anhydride, acid halide, activated amide, activated ester, activated thioester, etc. to react with fumagillol.
These reactive derivatives are specifically described as follows.
i) Acid halide :
For example, acid chlorlde, acid bromide, etc. are employed.
ii) Acid anhydride :
For example, symmetric acid anhydrides, mixed acid anhydrides with a lower alkyl carbonate, etc. are employed.
iii) Active amide :
For example, amides with pyrazole, imidazole, 4-substituted imidazole, dimethyl pyrazole, benzotriazole, etc. are employed.
iv) Active ester :
For example, besides esters such as methoxymethyl ester, benzotriazole ester, 4-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, etc., are employed esters with 1-hydroxy~lH-2-pyridone, N-hydxoxysuccinimide, N-hydroxyphthalimide, etc.
v) Active thioester :
For example, thioesters with heterocyclic thiol such as 2-pyridyl thiol, 2-benzothiazolyl thiol, etc.
are employed.
A reaction derivative of the carboxylic acid is employed in an amount of usually about 1 to 10 times as much mol., preferably 1 to 5 times as much mol., relative to 1 mol. of fumagillol. And, in case of using the carboxylic acid as its free state, the reaction is conducted preerably in the p.resence of a condensing agent. As the condensing agent, use is made of, for example, N,N~-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N
cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide, N-ethyl-N'-t3-dimethylaminopropyl)carbodiimide, diphenylphospholylazide, diethyl cyanophosphate, etc.
, 2 ~
This reaction is carried out usually in the presence of a base. As the base, use is made of the bases mentioned in the description of the alkylation, and the amount to be added ranges from about 1 mol. to 10 times as much mol. relative to 1 mol. of fumagillol.
This reaction is carried out usually in an organic solvent which does not e~ert undesirable influence on the reaction. As such organic solvents, use is made of those mentioned in the description of the alkylation.
The reaction temperature varies with the amount, kinds, etc. of carboxyli.c acid derivatives, bases and solvents, but it ranges from -~0C to 100C, preferably from 0C to 80C. The reaction time ranges from about 30 minutes to about 5 days.
lS 3) Carbamoylation :
Carbamoylation for introducing a mono-substituted carbamoyl group is carried out by usually allowing isocyanate to react with fumagillol.
This isocyanate is used in an amount of usually about 1 mol. to about 5 times as much mol. relative to 1 mol. of fumagillol This reaction may be conducted in the presence of a base. As the base, use is made of bases mentioned in the description of the alkylation in an amount ranging 25` from about 1 mol. to 10 times as much mol. relative to 1 mol. of fumagillol.
This reaction is carried out usually in an organic solvent which does not exert undesirable influence on the reaction. As such organic solvents as above, use is made of those mentioned in the description of the alkylation.
The reaction temperature varies with the amounts and kinds of isocyanate, the base and the solvent then employed, and it usually ranges from about -80C to 100C, preferably from 0C to 80C. The reaction time ranges from about one hour to about five days.
2 ~
Among the compounds having mono-substituted carbamoyl group thus obtained, compounds having, for example, chloroacetyl carbamoyl, trichloroacetyl carbamoyl, etc., can be converted t.o compounds having S carbamoyl c3roup by removing chloroacetyl group or trichloroacetyl group by a conventional process (e.g.
at room temperatures or elevated ~emperatures und0r basic conditions).
~lhe said carbamoylation can also be conducted by allowing fumagillol to react with carbamoyl halide.
The said carbamoyl halide is used in an amount usually ranging from l mol. to 5 times as much mol.
relative to 1 mol. of fumagillol.
This reaction is carried out usually in the presence of a base. As the base, use is made of bases mentioned in the description of the alkylation, and the amount of the base to be added ranges usually from about 1 mol. to about lO times as much mol. relative to 1 mol. of fumagillol.
This reaction is carried out usually in an organic solvent which does not exert undesirable influence on the reaction. Examples of such organic solvents as abo~e include those mentioned in the description of the alkylation.
The reaction temperature vary with the amounts and kinds of carbamoyl halide, bases and solvents, and it ranges from about 0C to around the reflux temperature of the reaction medium, preferably from about 25C to reflux temperature.
The said carbamoylation can also be carried out by allowing the 1,1-carbonyldiimidazole to react with the fumagillol to give an active ester, followed by allowing the ester to react with ammonia, primary amines (e.g. methylamine, ethylamine, isopropylamine, etc.), or secondary amine (e.g. dimethylamine, ; ethylmethylamine, dimethylamine, pyrrolidine, 2~1k3 piperidine, N-methylpiperazine, morpholine, etc.).
1,1-Carbonyldilmidazole, ammonia, primary amines and secondary amines are employed in an amount ranging from usually 1 mol. to 5 times as much mol. relative to S 1 mol. of fumagillol.
This reaction is carried out usually in an organic solvent which does not exert undesirable influence. As such organic solvents, use is made of those mentioned in the description of the alkylation.
While the reaction temperature varies with the amounts and kinds of ammonia, primary amines, secondary amines and solvents, it ranges from -20C to the reflux temperature o~ the reaction medium, preferably from 0C
to 50C. The reaction time ranges from 20 minutes to about 5 days.
Incidentally, the active esters obtained as intermediates are included in the category of the compound (III).
Among the compound ~III) wherein G is a mono-substituted carbamoyl group, a compound (III) wherein is a substituted lower alkanoyl carbamoyl group can also be prepared by allowing a compound (III) wherein G
is chloroacetyl carbamoyl to react with a nucleophilic reagent.
As the nucleophilic reagent, use is made of a lower carboxylic acid, a lower thiocarboxylic acid, thiols, amines and metal salts of them, and the amount of such reagent ranges usually from about 1 mol. to about 20 times as much mol. relative to 1 mol. of the starting compound, preferably from 1 mol. to 5 times as much mol.
This reaction is conducted usually in the presence of a base. As the base, use is made of those mentioned in the description of the alkylation, and its amount to be added ranges usually from about 1 mol. to 10 times as much mol. relative to 1 mol. of the starting - 23 - ~ ~2 compound.
This reaction is usually carried out in an organic solvent which does not exert undesirable i.nfluence on the reaction. As the organic solvents exertin~ rlo undesirable in1uence on ~he reaction, use is made of those mentioned in the clescription of the alkylation.
While the reaction temperature varies with the amounts, kinds, etc. o the nucleophilic reagents, bases and solvents, it ranges usually from -80C to lOO~C, preferably from 0C to 80C. The reaction time ranges from about 20 minutes to 5 days.
4) Thiocarbamoylation In the above-mentioned carbamoylation~ by conducting similar reaction employing thioisocyanate in place o~ isocyanate, a derivative into which mono--substituted thiocarbamoyl group is introduced can be synthesi.zed.
5) Sulfonylation This sulfonylation is carried out by allowing fumagillol to react with, for example, sulfonic anhydride, an activated sulfonic acid derivative such as sulfonyl halide (e.g. sulfonyl chloride, sulfonyl bromide, etc.) or an activated sulfamic acid derivative such as sulfamoyl halide (e.g. sulfamoyl chloride, sulfamoyl bromide, etc.
The said reactive derivatives of the sùlfonic acid are employed in an amount usually ranging from about 1 mol. to 5 times as much mol. relative to 1 mol. of fumagillol.
This reaction is conducted usually in ~he presence of a base. As the base, use is made of those mentioned in the description of the alkylation, and the amount to be added ranges usually from about 1 mol. to 10 times as much mol. relative to 1 mol. of fumagillol.
This reaction is carried out usually in an organic solvent which does not exert undesirable influence on - ` 2 ~
the reaction. As the organic solvent which does not exert undesirable influence on the reaction, use is made of those mentioned in the description of the alkylation.
While the reaction temperature varies with the amounts of sulfonic acid or the amount and kinds of sulfamic acid derivatives, bases and solvents, it ranges usually from -80C to 100C, preferably from 0C
to 80C. The reaction time ranges from about 10 minutes to about 5 days.
The said reactive derivatives of the sùlfonic acid are employed in an amount usually ranging from about 1 mol. to 5 times as much mol. relative to 1 mol. of fumagillol.
This reaction is conducted usually in ~he presence of a base. As the base, use is made of those mentioned in the description of the alkylation, and the amount to be added ranges usually from about 1 mol. to 10 times as much mol. relative to 1 mol. of fumagillol.
This reaction is carried out usually in an organic solvent which does not exert undesirable influence on - ` 2 ~
the reaction. As the organic solvent which does not exert undesirable influence on the reaction, use is made of those mentioned in the description of the alkylation.
While the reaction temperature varies with the amounts of sulfonic acid or the amount and kinds of sulfamic acid derivatives, bases and solvents, it ranges usually from -80C to 100C, preferably from 0C
to 80C. The reaction time ranges from about 10 minutes to about 5 days.
6) Oxycarbonylation Oxycarbonylation i5 also conducted by allowing a chloroformic acid ester (e.g. phenyl chloroformate, ethyl chloroformate, isobutyl chloroformate, ben~yl chloro~ormate, l-chloroethyl chloroformate, etc.) to react with fumagillol. The chloroformic acid ester is used usually in an amount of 1 mol. to 5 times as much mol~ relative to 1 mol. of fumagillol.
This reaction is conducted usually in the presence of a base. As the base, use is made of those mentioned in the description of the alkylation, and the amount to be added ranges usually from about 1 mol. to 10 times as much mol. relative to 1 mol. of fumagillol.
This reaction is conducted usually in an organic solvent which does not exert undesirable influence on the reaction. As the organic solvent which does not - exert undesirable influence on the reaction, use is made of those mentioned in the description of -the~
alkylation.
While the reaction temperature varies with the ~
amounts, kinds, etc. of chloroformic acid ester, bases and solvents, it ranges from -20C to the reflux temperature of the reaction medium, preferably from 0C
to 50C. The reaction time ranges from about 10 minutes to about 5 days.
And, the compound (III) wherein G i mono- and di-2 ~
~s substituted carbamoyl can be produced also by allowing the compound (III) wherein G is phenoxycarbonyl to react with ammonia, primary ~mines (e.g. methylamine, ethylamine, isopropylami.ne, etc.), or secondary amines (e.g. dimethylamine, ethylmethylamine, dimethylami.ne, pyrrolidine, piperidine, N-methylpiperazine, morpholine, etc.).
Ammonia, primary amines and secondary amines are employed usually in an amount of 1 mol. to 5 times as much mol. relative to 1 mol. of the starting compound.
This reaction is conducted usually in an organic solvent which does not exert undesirable influence on the reaction. As the organic solvent which does not exert undesirable influence, use is made of those mentioned in the description of the alkylation.
~ hile the reaction temperature varies with amounts, kinds, etc. of ammonia, primary amines, secondary amines and solvents, it ranges from -20~C to the reflux temperature of the reaction medium, preferably from 0C to 50C. The reaction times ranges from about 20 minutes to about 5 days.
Reaction step 2. Production of the compound (IV) from fumagillol (II) This reaction can be conducted by, for example in the acylation described in the acylation in the reaction step l, using acid halide as the reactive derivative of carboxylic acid and, as the base, triethylamine or pyridine.
Reaction step 3: Production of the compound (V) from fumagillol (II) This reaction can be conducted by allowing hydrogen halide to react with fumagillol.
Examples of the hydrogen halide include hydrogen bromide, hydrogen iodide, etc., and they are used as an aqueous solution of hydrobromic acid, hydroiodic acid, etc. in general. The hydrogen halide is used in an amount of usually about 1 mol. to 10 times as much mol., preferably 1 to 5 times as much mol. relative to 1 mol. of fumagillol.
This reaction is conducted usually in a sol~ent S which does not exert undesirable influence on the reaction. As the solve~t which does not exert undesirable influence on the reaction, use is made of, for example, water, and alcohols, amides, halogenated hydrocarbons, ethers, esters, nitriles, nitro compounds, ketones, aromatic hydrocarbons, aliphatic hydrocarbons, etc. referred to in the reaction step 1.
These can be used singly or as a suitable combination of two or more species of them.
While the reaction temperatures vary with the amounts, kinds, etc. of hydrogen halide and solvents, they are in the ran~e from -80 to 100C, preferably from 0C to room temperatures (room temperatures mean the range from about 20 to about 35C, and the same applies hereinafter unless otherwise specified). The reaction time ranges from about 30 minutes to about 5 days.
And, the reaction with hydrogen iodide may be conducted in accordance with a ~ se known method [Cornforth, J. W., et al., J. Chem. Soc., 1959, 112].
Reaction step 4: Production of the compound (VI) from fumagillol (II) This reaction is conducted by allowing secondary amines or thiols to react with fumagillol.
As the secondary amines or the thiols, use is made of HNRlR2, HSRl wherein Rl and R2 are of the same meaning as defined for them in the general formula (I), or metal salts thereof, and, as the metal salt, use is made of salts with, for instance, aIkali metals (e.g.
lithium, sodium, potassium, etc.), etc.
The secondary amines or the thiols are used in an amount of usually ranging from about 1 mol. to about 10 . .
'J
times as much mol., preferably 1 to 5 times as much mol., xelative to 1 mol. of fumagillol.
This reaction may be conduc-ted in the presence of a bas0. ~s the base, use is made of tertiary amine, alkali met~l h~drogencarbonates, alkali metal carboantes, alkali metal hydrides, etc. mentioned in the reaction step 1, and the amount to be added ranges usually from about 1 mol. to 10 times as much mol.
relative to 1 mol. of fumagillol.
This reaction is conducted in the absence of solvent or in a solvent which does not exert undesirable influence on the reaction. As the solvent which does not exert undesirable influence, use is made of, for example, solvents referred to in the reaction step 3.
The reaction temperature varies with the amounts, kinds etc. of secondary amines, thiols, bases and solvents, but it ranges from -80C to 100C, preferably from 0C to 50C. The reaction time .ranges from about 30 minutes to about 5 days Reaction step 5: Production of the compound (IV) from the compound (III) This reaction can be conducted by subjecting the compound (III) to the reaction mentioned in the reaction step 3, and, in the reaction mentioned in the reaction step 3, hydrogen chloride or hydrochloric acid may be used as hydrogen halogenide.
Reaction step 6: Production from the compound (IV) ~rom the compound (~) This reaction can be conducted by subjecting the compound (V) to the reaction mentioned in the reaction step 1.
React,ion step 7: Production of the compound (VI) ~rom the compound (V) This reaction can be conducted by subjecting the compound (V) to the reaction mentioned in the reaction ~J~L~
_ 2~ -step 4.
Reaction step 8: Production O:e the compound (VII) from the compound (III) This reaction can be conducted b~ subjecting the compound (III) to the reaction mentioned in the reaction step ~.
Reaction s~ep 9: Production of the compound (VII) from the compound (IV) This reaction can be conducted by subjecting the compound lIV) to the reaction mentioned in the reaction step 4.
Reaction step 10: Production of the compound (X) from the compound (IV) This reaction can be conducted by allowing tertiary amines or sulides to react with the compound (IV).
As the tertiary amines or the sulfides, use is made of NRI~2R3 or SRlR2 wherein RI~R3 are of the same meaning as defined for those in the general formula (I).
The tertiary amine or the sulfides are used in an amount of usually about 1 mol. to 10 times as much mol., preferably 1 to 5 times as much mol., relative to a mol. of the compound (IV).
This reaction can also be conducted in the presence of a base or metal salt. As the base, use is made of the afore-mentioned alkali metal hydrogencarbonates, alkali metal carbonates, etc., and, as the metal salt, use is made of mercury salts (e.g.
mercury iodide, etc.) or silver salts (e.g. silver tetrafluoroborate, silver perchlorate, etc.), etc., and the amount to be added ranges usually from about 1 mol.
to 5 times as much mol. relative to 1 mol. of the compound (IV).
This reaction is conducted in the absence of solvent or in an organic solvent which does not exert 2 ~ v ~
undesirable influence. As the organic solvent which does not exert undesirable influence, use is made of alcohols, ami.des, haloger~ated hydrocarbons, ethers, esters, nitriles, nitro compounds, ketones, aromatic S hydrocarbons, aliphatic saturated hydrocarbons, etc.
mentioned in the reaction step 1, and these solvents may be used singly or as a mixture of two or more of them in a suitable ratio.
The reaction temperature varies with the amount, kinds, etc. of tertiary amines, sulfides, bases, metal salts and solvents, but it ranges from -80C to 100C, preferably from 0C to 50C. The reaction time ranges from about 30 minutes to about 15 days.
Reaction step 11: Production of the compound ~VIII) from the compound (V) This reaction can be conducted by subjecting the compound (V) to the reaction described in the reaction step 10.
Reaction step 12: Production of the compound (VII) from the compound (VI) This reaction can be conducted by subjecting the - compound (VI) to the reaction described in the reaction step 1.
Reaction step 13: Production of the compound (VIII) from the compound (VI) This reaction is conducted by subjecting the compound (VI) to N or S alkylation.
The said alkylation is conducted by allowing an alkylating agent represented by R3J wherein R3 is o~
the same meaning as defined for R3 in the general formula (I), and J stands for a leaving group such as halogen, methanesulfonyloxy group, p-toluenesulfonyloxy group, methoxysulfonyloxy group, trifluromethanesulfonyloxy group, dimethyloxonio-tetrafluoroborate group, diethyloxonio-tetrafluoroborate group, etc. to react 2 ~
with the compound (VI).
The alkylating agent is used usually in a range of from about l mol. to 100 times as much mol. relative to 1 mol. of the compound (VI).
This reaction may be conducted in the presence of a base or a metal salt. As the base, use is made of alkali me~als hydrogencarbonates, alkali metal carbonates, etc. mentioned in the reaction step 1, and, as the metal salt, use is made of mercury salt (e.g.
mercury iodide, etc.), and the amount of such base to be added ranges from about 0.1 mol. to 5 times as much mol. relative to l mol. of the starting alcohol.
This reaction is conducted in the absence of solvent or in an organic solvent which does not exert undesirable influence on the reaction. As the organic solvent which does not exert undesirable influence on the reaction, use is made of amides, halogenated hydrocarbons, ethers, esters, nitriles, nitro compounds, ketones, aromatic hydrocarbons, aliphatic ~0 hydrocarbons, etc., and these can be used singly or as a mixture of two or more of them in a suitable ratio.
The reaction temperature varies with the amounts, kinds, etc. of the alkylating agents, ~ases, metal salts and solvents, but it ranges from -80C to 100C, preferably from 0C to 50C. The reaction time ranges ; from about 20 minutes to about 5 days.
Reaction step 14: Production of the compound (IX) from the compound (VI) This reaction is conducted by subjecting NRlR2 group or SR3 group shown by X in the compound (VI) to oxi.dation.
As the oxidizing agent to be employed for ~he oxidation, use is made of aqueous hydrogen peroxide, periodic acid (e.g. ortho periodic acid, meta periodic acid, etc.) or salts thereof, organic peracids te.g.
performic acLd, peracetic acid, perbenzoic acid 2 ~
methachloroperbenzoic ~cid, etc.) or salts thereof.
This reaction is conducted usually in a solvent which does not exert undesirable influence on the reaction. ~s the solvent which does not exert undesirable in~luence on the reaction, use is made of water, and halogenated hydrocarbons, ethers, aromatic hydrocarbons or aliphatic saturated hydrocarbons mentioned in the reaction step l. These solvents may be used singly or a mixture of two or more of them in a suitable ratio.
The reaction temperature varies with the amounts, kinds etc. of the oxidizing agents and solvents, but it ranges ~rom -80C to 100C, preferably from 0C to 50C. The reac~ion time ranges from about 20 minutes ko 5 days.
Reaction step 15: Production of the compound (X) from the compound (VII) This reaction can be conducted by subjecting the compound (VII) to the reaction described in the -eaction step 13.
Reaction step 16: Production of the compound (X) from the compound (~III) This reaction can be conducted by subjecting the compound (VIII) to the reaction described in the reaction step 1.
Reaction step 17: Production of the compound (XI) from the compound (VIII) This reaction can be conducted by subjecting a compound (VIII) wherein M stands ~or S~RlR2-X~ to the reaction described in the reaction step 14.
Reaction step 18: Production of the compound (XI) from the Compound (IX) This reaction can be conducted by subjecting a compound (IX) wherein L is S(O)Rl to the reaction described in the reaction step 11.
Reaction step 19: Production of the compound (XII) from the compound (IX) This reaction can be conducted by subjecting the compound (IX) to the reaction described in the reaction step 1.
Reaction step 20: Product.ion of the compound (XIII) from the compound (X) This reaction can be conducted by subjecting a compound (X) wherein M is S~RlR2-X~ to the reaction described in the reaction step 14.
Reaction step 21: Production of the compound (XIII) from the compound (XI) This reaction can be conducted by subjecting the compound (XI) to the reaction described in the reaction step 1.
Reaction step 22: Production of the compound (XIII) from the compound (XII) This reaction can be conducted by subjecting a compound (XII) wherein L is S(O)RI to the reaction described in the reaction step ll.
Reaction step 23: Production of the compound (XII) from the compound (VII) This reaction can be conducted by subjecting the compound (VII) to the reaction described in the reaction step 14.
Reaction step 24: Production of the compound (XIV) from fumagillol (II) This reaction is conducted by subjecting fumagillol to oxidation using chromic anhydride in pyridine in accordance with, for example the method of Tarbell e~ al. [Tarbell, D.S.,(J. Am. Chem. Soc.), 77, 5610 (1955)], or to oxidation using pyridinium dichromate in accordance with the method of Goto et al~
(JPA Sho 62-476).
And, in accordance with per se known methods, Jones oxidation [Jones. E.R.H., (J. Chem. Soc.), 1946, 39], Collins oxidation [Collins, J.C., Tetrahedron - .
-` 2 ~ 2 ~
Lett., 1968, 3363], PCC oxidation [Corey, E.J., et al., Tetrahedron Lett., 1975, 2647] or oxidat.ion using the combination of dimethylsulfoxide and an activating agent may be conducted. ~s the activatin~ agent. for dimethylsulfoxide, use can be made of dicyclohexylcarbodiimide [Moffat, J.G., et al. ~. Am.
Chem. Soc., 85, 3027 (1963)], acetic anhydride [Albright, J.D., et al., J. Am. Chem. Soc., 87, 4214 tl965)], phosphorus pentoxide [Onodera et al. J. Am.
Chem. Soc.), 87, 4214 (1965)], sulfur trioxide -pyridine complex [Parikh, J.R., et al., J. Am. Chem.
Soc., 89, 5505 ~1967)], oxalylchloride [Swern, D., et al., J. Org. Chem., 43, 2480 (1978)], etc.
Reaction step 25: Production o~ the compound (XVII) from the compound (XIV) This reaction is conducted by subjecting the compound (XIV), in accordance with a Per se known method [Borch, R.F. et al. ~. Am. Chem. Soc., 93, 2897 (1971)], to reductive amination.
Reaction step 2~: Production of the compound (XV) from fumagillol (II) This reaction can be carried out, in accordance with the scheme 1, by subjecting fumagillol to an~ one of the reactions described in the reaction steps 3, 4, 11, 13, 1~, 17 and 18, or to a suitable combination of them.
Reaction step 27: Production of the compound (XVI) from the compound (2IV) This reaction can be carried out, in a manner similar to the scheme 1, by subjecting the compound (XIV) to any one the reactions described in the reaction steps 3, 4, 11, 13, 14, 17 and 18, or to a suitable combination of them.
Reaction step 28: Production of the compound (XVI) from the compound (XV) This reaction can be carried out by subjecting the 2 ~ d ~
compound (XV) to the reaction described in the reaction step 24. And, transformation o~ the portion ~ may be carried out simultaneously by a suitable combination o the reacti.on described in the reaction step 24 with any o the re~ctions described in the reaction steps 9, 10, 13, 14, 17 and 18.
Reaction step 29: Production of the compound (XIX) from the compollnd (XVI) This reaction can be conducted by subjecting the compound (XVI) to the reaction described in the reaction step 25. And, transformation of the portion A
may be carried out simultaneously by a suitable combination o~ the reaction described in the reaction step 25 with any one of the reactions described in the reaction steps 9, 10, 13, 14, 17 and 18.
Reaction step 30: Production of the compound (XVIII) from the compound (XVII) This reaction can be conducted, in a manner similar to the scheme 1, by subjecting the compound (XVII) to the reaction described in the reaction step 1.
And, in the case of conducting alkylation of the NHR4 group of the compound (XVII), other than the method described in the reaction step 1, a method known as a reductive alkylation [Emoersonr ~.S., Org. React., 4, 174 (1948); or Lane, C.F., Synthesis, 135 (1975)]
may be employed.
Reaction step 31: Production of the compound (XIX) from the compound (XVII) This reaction can be conducted by subjecting the compound (XVII) to the reaction descri~ed in the reaction step 27.
Reaction step 32: Production of the compound (XX) from the compound (XIX) This reaction can be conducted by subjecting the compound (XIX) to the reaction described in the 2~2~3~3 reactlon step 30. And, transformation of the portion A
may be carried out simultaneously by a suitable combinat.ion of the xeaction described in the reaction step 30 with any one of the reactions described in the reaction steps 9, 10, 13, 14, 17 and 18.
Reaction step 33: Production of the compound (XX) from the compound (XVIII) This reaction can be carried out, in a manner similar to the scheme 1, by subjecting the compound (XVIII) to any one of the reactions described in the reaction steps 5, 8, 9, 10, 15, 20, 22 and 23, or to a suitable combination of them.
Reaction step 34: Production of the compound (XXI) from fumagillol This reaction is conducted by subjecting a 6-O-acyl-6-epifumagillol derivative to hydrolysis by a per se known method [~ose, A.K., Tetrahedron Lett., 1973, 1619], the derivative being obtained by sub~ecting fumagillol to the Mitsunobu reaction using diethyl azodicarboxylate and carboxylic acid such as triphenyl phosphine and formi.c acid or benzoic acid [Mitsunobu, O., Synthesis, 1 (19~1)].
Reaction step 35: Production of the compound (XXIII) from the compound (XV) This reaction can be conducted by subjecting the compound (XV) to the reaction described in the reaction step 34. And, trans~ormation of the portion A can be conducted simultaneously by suitable combination of the reaction described in the reaction step 34 with any one of the reactions described in the reactions steps 9, 10, 13, 14, 17 and 18.
Reaction step 36: Synthesis of the compound (XXII) from : the compound (XXI) This reaction can be conducted by subjecting the compound (XXI) to the reaction described in the reaction step 1.
2~3~
Reactlon step 37: Synthesis of the compound (XXV) from the compound (XXIII) This reaction can be conducted by subjecting the compound (XXIII) to a reaction similar eo that described in the reaction step 1. And, transformation of the portion A may be carried out simultaneously by a suitable combination of the reaction described in the reaction step 1 with any one of the reactions described in the reaction steps 9, 10, 13, 14, 17 and 18.
Reaction step 38: Synthesis of the compound (XXIII) from the compound (XXI) This reaction can be conducted by subjecting the compound (XXI) to the reaction described in the reaction step 27.
Reaction step 39: Production o~ the compound (XXIV) from the compound (XXII) This reaction can be conducted by subjecting the compound (XXII) to the reaction described in the : reaction step 33.
Reaction step 40: Production of the compound (XXV) from fumagillol (II) This reaction is conducted by subjecting an imide compound to hydrolysis by means of a ~E se known method [Mitsunobu, O., J. Am. Chem. Soc., 94, 679 (1972)], the imide compound being obtained by subjecting fumagillol to Mitsunobu reaction using diethyl azodicarboxylate, triphenyl phosphine and imide such as phthalimide or succinimide [Mitsunobu, O., Synthesis, l (1981)].
Reaction step 41: Production of the compound (XXIX) from the compound ~XV) This reaction can be conducted by subjecting the compound (XV) to the reaction described in the reaction step 40. And, transformation of the portion A may be simultaneously carried out by sui~able combination of the reaction described in the reaction step 40 with any ~2~
.
one of the reactions described in the reaction steps 9, 10, 13, 14, 17 and 18.
~eaction step 42: Production of the compound (XXIX) ~rom t:he compound (XXV) This reaction can be conducted by subjecting the compound (XXV) to the reaction described in the reaction step 27.
Reaction step 43: Production of the compound ~XXVII) ~ro the compound (XXV) This reaction can be conducted by subjecting the compound (XXV) to N-alkylation by means of a Per se known method ["Comprehensive Organic Chemistry~ Vol. 2, pp. 4 to 11, compiled by Sutherland, I.O., Pergamon Press (1979)].
Reaction step 44: Production of the compound ~XXXI) from the compound (XXIX) This reaction can be conducted by subjecting the compound (XXIX) to the reaction described in the reaction step 43. And, transformation of the portion A
may be carried out by a suitable combination of the reaction described in the reaction step 43 with any one of the reactions described in the reaction steps 9, 10, 13, 14, 17 and 1~.
Reaction step 45: Production of the compound (XXXI) from the compound (XXVII) This reaction can be conducted by subjecting the compound (XXVII) to the reaction described in the reaction step 27.
Reaction step 46: Production of the compound (XXVI) from the compound (XXV) This reaction can be conducted by subjecting the compound (XXV) to the reaction described in the reaction step 30.
Reaction step 47: Production of the compound (XXX) from the compound (XXIX) This reaction can be conducted by subjecting the 2~2~`~3~
compound (XXIX) to the reaction clescribed in the reaction step 30.
Reaction step ~: Production of the compound (XXX) from the compound (XXVI) rrhis reaction can be conducted by subjecting the compound (XXVI) to the reaction described in the reaction step 33.
Reaction step 49: Production of the compound (XXVIII) from the compound (XXVII) This reaction can be conducted by subjecting the compound (X~VII) to the reaction desc.ribed in the reaction step 30.
Reaction step 50: Production of the compound (XXXII) from the compound (X~XI) ~his reaction can be conducted by subjecting the compound (XXXI) to the reaction described in the reaction step 30. And, transformation of the portion A
may be carried out simultaneously by a suitable combination of the reaction described in the reaction step 30 with any one of the reactions described in the reaction steps 9, 10, 13, 14, 17 and 13.
Reaction step 51: Production of the compound (XXXII) from the compound (XXVIII) This reaction can be conducted by subjecting the compound (XXVII) to the reaction described in the reaction step 33.
When substituents such as amino group, lower alkyl amino group, hydroxyl group and carboxyl group are 3~ present on starting compounds to be employed in the afore-described methods and on acylating agents, carbamoylating agents, alkylating agents and sylfonylating agents to be employed in these methods, the reaction can be allowed to proceed advantageously by having these substituents protected previously.
For the protection and deprotection of these ~2~
- 3g -substituents, a per se known method [Greene, T.W., "Protective Group in Organic Synthesis", John Wiley &
Sons, New York (1981)] can be used.
Thus-produced compounA (I) of the present invention can be isolated by, for example, ~ 9e known separating and reining means (e.g. chromatography, crystallization). ~nd, in the case o the compound (I) containing counter anion shown by X~, exchange of the counter anion can be conducted by processing with, for example, ion-exchange resin or silver salt (e.g. silver oxide, silver acetate, silver perchlorate, etc.).
The compounds of this invention show an action of inhibiting angiogenesis and and an anti-tumor activity, and are useful as therapeutic and prophylactic agents of various inflammatory diseases (rheumatic diseases, psoriasis), diabetic retinopathy or tumors, and their toxicity is relatively low. ~nd, they can be safely administered orally or non-orally as they are or as a pharmaceutical composition prepared by mixing with Per se known pharmaceutically acceptable carriers, excipients, etc. [e.g. tablets, capsules (including soft capsules, microcapsules), liquidsr injections, suppositories]. The dosage varies with, among others, subjects, routes and symptoms, but, usually, it ranges, in an adult, from about 0.1 mg/kg to about 40 mg/kg body weight, preferably from about 0.5 mg/kg to about 20 mg/kg body weight per day.
Pharmacological effects of the compounds of this invention are described as follows.
Experimental Example 1 Angiogenesis inhibitory action by the rat cornea micropocket method Method of Evaluation :
Essentially the same method of Gimbrone et al. [J.
National Cancer Institute 52:413-419 (1974)~ was followed.
2 ~ 3 ~ ~) Thus, adult male Spra~ue-Dawley rats (11 to 16 week old) were anesthetized with nembtal and locally anesthetized hy instillation of xylocaine eyedrops onto the eyeball. The cornea was incised to a length of about 2 mm at about 2 mm inside from the corneal c.i.rcumference by means of an injection needle, and a basic fibroblast growth factor (bFGF, bovine brain-derived, purified product, ~ & D Inc.) and a sustained xelease pellet containing the test sample were inserted side by side into the incision so that the bFGF pellet was located on the central side in the cornea. In the control group, the bFGF pellet and a sample-free pellet we.re inserted into the cornea. After 10 days, the cornea was observed under a stereoscopic microscope.
The results are shown in Table 1.
The sustained release pellets were prepared in the following manner. An ethylene-vinyl acetate copolymer (Takeda Chemical Industries, Ltd.) was dissolved in dichloromethane to a concentration of 8%. A 3 ~1 portion of the solution was air-dried on a glass dish, an aqueous solution of bFGF (250 ng) was then placed thereon and air-dried and, finally 3 ~1 of the above-mentioned ethylene-vinyl acetate copol~mer solution was placed further thereon and air-dried to give a sandwich sheet. This sandwich sheet was made round into a bFGF
pellet. The test sample pellets were prepared by dissolving each sample in ethanol to a concentration of 20 ~g/2 ~1, mixing the solution with 6 ~1 of an ethylene-vinyl acetate copol~mer solution, air-drying the mixed solution on a glass dish and making the thus-obtained sheet round.
`` 2 ~
Table 1 Angiogenesis Inhibitory Activity Compound (~xample No.) Inhibitory Rate Judgment lc S/5 4 3/5 +
~8 4/7 Incidentally, in the above Table 1, the numbex of rats subjected to the test was shown by denominator, and the number of rats whose angiotensin due to bFGF
was retarded or weakened by administration of the test sample was shown by numerator. In the judgment, +
means an inhibit.ion rate of 70% or more, and ~ means that of less than 70% but exceeding 40%.
Experimental Example 2 C57BL/6 mice (a group consisting of 6 mice) were inoculated subcutaneously at the dorsolateral area with 2 x 106 M5076 cells, and then a test compound dissolved in a 5% gum arabic physiological saline solution was subcutaneously administered lO times in total, i.e.
1st, 2nd, 4th, 5th, 6th, 7th, 8th, 9th, 11th and 12th day after the inoculation. After 13 days, the major axis (a) and the minor axis ~b) of the tumor tissue were measured to determine the tumor size by the calculation formula of a x b2 x 1/2. The ratio of the tumor size thus calculated to the tumor size of animals in the control group was shown by T/C (~). The results are shown in Table 2.
:
2 ~
~ 42 -Table 2 Compound (Example No.) Dose (mg/kg) T/C(%) lc 30 20 : 15 76 20 29 104 ~0 16 Examples By the following Reference Examples and Examples, the present invention will be described in more detail, but the present invention is by no means limited to these examples.
The elution in the column chromatography in the following Reference Examples and Examples (bracketed terms are solvents for elution) is conducted under observation by means of thin layer chromatography (TLC).
In the TLC observation, as the TLC plate, Kieselgel 60F250 (70 to 230 mesh, Merck) was employed, as the developing solvent, the one employed for elution in the column chromatography, and, as the method of detection, a UV detector, a color-development method with phosphorus molybdate, etc. were employed. As the silica gel for the column, ~ieselgel 60 (70 to 230 ~ a 2 ~
mesh, Merck) ~as employed. NMR spectrum shows proton N~R(IH~NMR), and, as interior or exterior standard, tetramethylsilane was employed, and the measurement was carri.ed out by using Gemini 200 (VARIAN) showing the value in terms of ppm.
Incidentally, abbreviations used in Reference Examples and Examples have the following significances, respectively.
s:singlet, br:broad, d:doublet, dd:double doublet, ddd:doublet doublet doublet, t:triplet, q:quartet, m:multiplet, ABq:AB quartet, J:coupling constant, Hz:Hertz, %:weight %.
And, the term "room temperatures" appearing in the following reference examples and working examples means temperatures ranging from about lS to 25C. Melting points and temperatures are all shown by cent~grade.
In the description of compound names in the following Reference Examples and Examples, portion of the absolute steric configuration was omitted as it was in agreement with that of ft~agillol. Referring to the relative steric configuration, only the portion different from that of fumagillol based on the structural formula shown for Compound (I) was described.
Reference Example 1 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1,4-cyclohexanediol To a solution of fumagillol (200 mg) in ethanol (2 ml) was added 0.5N hydrochloric acid (1 ml), and the mixture was stirred at room temperatures for one hour.
To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate to neutralize, which was concentrated under reduced pressure. The concentrate was purified by means of a silica gel column chromatography (carrier 10 g, developing ~2~i3~
- 44 ~
solvent:hexane-ethylacetate=3:1) to give 2-(1,2-epoxy~
1,5-dimethyl-4-hexenvl)-3-me-thoxy-1-(chloromethyl)-1,4-cyclohexanediol (200 mg: yield 90~).
NMR spectr~m (~ value;CDC~3) : 1.33(1H,m), 1.49(3H,s), 1.67(3H,s), 1.75(3H,s), 1.5 to 2.6(7H,m), 2.99(1H,t,6Hz), 3.2 to 3.4(1H,m), 3.35(3H,s), 3.50(1H,d,llHz), 3.90(1H,br s), 4.23(1H,m), 5.19(1H,m).
Reference Example 2 O chloroacetylcarbamoyl fumagillol To a solution of fumagillol (314 mg) in dichloromethane (5 ml) was added dropwise, under cooling with ice, chloroacetylisocyanate (160 mg), to which was then added dimethylaminopyridine (130 mg), followed by stirring at 0C ~or two hours. To the reaction mixture was added water, which was subjected to extraction with dichloromethane. The organic layer was washed with a saturated aqueous saline solution, then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica ~el colunln chromatography (carrier 20 g, developing solvent: ethylacetate-hexane=1:2) to afford O-chloroacetylcarbamoyl fumagillol (318 mg: yield 71%) as colorless powder.
NMR spectrum (~ value; CDC~3) : l.lO(lH,m), 1.21(3H,s), 1.66(3H,s), 1.75(3H,s), 1.93(1H,d,llHz), 1.8 to 2.5(5H,m), 2.57(1H,d,4Hz), 2.58(1H,m), 2.99(1H,d,4Hz), 3.47(3H,s), 3.58(1H,dd,llHz,3Hz), 4.44(2H,s), 5.20(1H,m), 5.61(1H,m), 8.33(1H,br s).
Reference Example 3 O-(p-toluenesulfonyl)fumagillol To a solution of fumagillol (3.00 g) and dimethylamino pyridine (3.24 g) in anhydrous dichloromethane (30 ml) was added p-toluenesulfonyl , - 2 ~
- 45 ~
chloride (3.04 g), and the mixture was stirred at room temperatures o~ernight. The reaction mixture was diluted with d.ichloromethane, washed with a saturated aqueous saline sol~tion, followed by drying over anhydrous magnesium sul-eate. The solvent WclS d.istilled off under reduced pressure, then the residue was purified by means of a silica gel column chromatography (carrier 150 g, developing solvent:ethyl acetate-hexane=1:2). The resulting crude crystals were recrystallization from diisopropylether to afford O-(p-toluenesulfonyl)fumagillol as colorless crystals (2.88 g : yield 62%). m.p.: 123 to 124C.
NMR spectrum (~ value; CDC~3) : 1.14(1H,m), 1.16(3H,s), 1.67(3H,s), 1.70(3H,s), 1.84(1H,m), 1.95(lH,d,llHz), 2.04 to 2.47(4H,m), 2.44(3H,s) t 2.55(lH,d,4Hz), 2.56(lH,t,6Mz), 2.94(lH,d,4Hz), 3.02(3H,s), 3.50(lH,dd,lOHz),2Hz), 5.07(lH,m), S.l9(1H,m), 7.33(2H,d,8Hz), 7.87(2H,d,8Hz).
Reference Example 4 O-phenoxycarbonyl fumagillol Fumagillol (133 mg) and dimethylaminopyridine ~115 mg) were dissolved in dichloromethane (3 ml). To the solution was added phenyl chloroformate (lll mg), and the mixture was stirred for 30 minutes at room temperatures. To the resultant was added water, which was diluted with dichloromethane (30 ml), followed by washing with water and a saturated aqueous solution of sodium chloride. The solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (carrier 10 g, developing solvent : n-hexane-ethyl acetate=5:1) to afford O-phenoxycarbonyl fumagillol (174 mg : yield 92%) as a colorless oily product.
NMR spectrum (~ value; CDC~3) : l.lO(lH,m), 1.22(3H,s), 1.66(3H,s), 1.75(3H,s), 1.8 to 2.45(6H,m), 2 ~J~'~ 3 ~3'X
2.56(1~,d,4Hz), 2.59(1H,-t,6Hz), 2.99(1H,d,4Hz), 3.50(3H,s), 3.69(1H,dd,llHz,3~Iz), 5.18(1H,m), 5.58(1H,br s), 7.15 to 7.45(5H,m).
Reference Example 5 6-O-formyl-6-epifumagillol F~lmagillol ~4.0 ~), triphenylphosphine (11.2 g) and formic acid (1.1 ml) were dissolved in tetrahydrofuran (100 ml). To the solution was added dropwise a solution of diethylazocarboxylate ~7.4 g) in tetrahydrofuran (20 ml). The mixture was stirred overnight, which was then diluted with eth~l acetate (300 ml), followed by washing with a saturated a~ueous solution of sodium chloride, then with a saturated aqueous solution of sodium hydrogencarbonate and further with a saturated aqueous solution of sodium chloride. The resultant was dried over anhydrous magnesium sulfate, then the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel chromatography (carrier 200 g, developing solvent : ethyl acetate-he~ane = 1:3) to af~ord 6-O-formyl-6-epifumagillol (2.6 g: yield 59%).
NNR spectrum (~ value; CDCQ3): 1.21(1H,m), 1.27(3H,s), 1.61(1H,d,llHz), 1.66(3H,s), 1.75(3H,s), 1.70 to 2.25(4H,m), 2.38(1H,m), 2.56(lH,m), 2.59(1H,d,4Hz), 2.98(1H,d,4Hz), 3.56(3H,s), 3.83(lH,dd,9Hz,llHz), 5.00(lH,m), 5.20(lH,m), 8.17(1H,s).
Reference Example 6 6-Epifumagillol - 6-O-formyl-6-epifumagillol (2.5 g) was dissolved in methanol (20 ml), to which was added conc.
ammoniacal water (5 ml), and the mixture was stirred for 15 minutes. The solvent was distilled o~f under reduced pressure, then the residue was dissolved in 2~2~
ethyl acetate (100 ml), which was washed with a saturated aqueous solution of sodium chloride. The resultant was dried over anhydrous ma~nesium sulfate, thell the solvent was distilled off under reduced pressure. The res.idue was puri~ied by means o a silica gel chromatoc3raphy (carrier 100 g, developing solvent : ethyl acetate-hexane = 2:1) to afford 6-epifumagil]ol (1~8 g: yield 79%).
NMR spectrum (~ value; CDCR3): 1.22(1~,m), 1.30(3H,s), 1.54(1H,d,11Hz), 1.66(3H,s), 1.75(3H,s), 1.70 to 2.25(4H,m), 2.38(1H,m), 2.54(1H,d,4Hz), 2.57(1H,t,7Hz), 2.91(1H,d,4Hæ), 3.54 to 3.80(2H,m), 3.61(3H,s), 5.20(1H,m).
Reference Example 7 6-0-phenoxycArbonyl-6-epifumagillol 6-Epiumagillol (0.53 g) and dimethylaminopyridine (0.46 g) were dissolved in dichlorom~thane (8 ml), to which was added phenyl chloroformate (0.45 g), followed by stirring at room temperatures for 30 minutes. To the resultant was added water, which was then diluted with dichloromethane (40 ml). Th0 resultant was washed with water and a saturated aqueous solution of sodium chloride, which was dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel chromatography (carrier 2S g, developing solvent : ethyl acetate - hexane = 1:5), followed by crystallization from ethanol to give 6-O-phenoxycarbonyl-6-epifumagillol (0.55 g; yield 82%).
m.p. 118 to 119C
NMR spectrum (~ value; CDC23) : 1.22(1H,m), 1.28(3H,s), 1.63(1H,d,llHz), 1.66(3H,s), 1.75(3H,s), 1.6 to 2.5(5H,m), 2.57(1H,t,7Hz), 2.59(1H,d,4Hz), 2.98(1H,d,4Hz), 3.65(3H,s), 3.84(1H,dd,9Hz,llHz), 4.88(1H,m), 5.20(1H,m), 7.1 to 7.5(5H,m).
~ ~ 2 ~
- ~8 -Reference Example 8 6-O-morpholinocarbonyl ~-epi.f~lmagillol 6-O-phenoxycarbon~1-6-epifumagillol (0.17 g) was dissolved in dichloromethane (~ ml), to which was added morpholine (1 ml), and the mixture was stirred at room temperatures for one day. The reaction mixture was diluted with ethyl acetate (30 ml), which was washed with a saturated aqueous solution of ammonium chloride and a saturated aqueous solutio~ of sodium chloride.
The resultant was dried over magnesium sulfate, then the solvent was distilled off under reduced pressure.
The residue was purified by means of a silica gel chromatography (carrier 20 g, developi~g solvent :
ethyl acetate - hexane - 1:2) to afford 6-O-morpholinocarbonyl-6-epifumagillol (0.13 g : yield 74%). m.p. : 139 to 1~0C
NMR spectrum (~ ~alue; CDC23): 1.20(1H,m), 1.26(3H,s), 1.66(3H,s), 1.75(3H,s), 1.6 to 2.6(7H,m), 2.58(1H,d,4Hz), 2.97(1H,d,4Hz), 3.50(4H,m), 3.54(3H,s), 3.67(4H,m), 3.80(1H,dd,9Hz,llHz), 4.87(1H,m), 5.~1(lH,m).
ReferPnce Example 9 6~-Phthalimido-6-desoxyfumagillol Fumagillol (1.0 g), triphenylphosphine (1.22 g) and phthalimide (0.57 mg) were dissolved in tetrahydrofuran (THF, 30 ml), to which was added dropwise a solution of diethyl azodicarboxylate (0.83 g) in THF (5 ml). The mixture was stirred ~or 30 minutes, which was then diluted with ethyl acetate (100 ml). The resultant was washed with a saturated aqueous solution of sodium chloride, then with a saturated aqueous solution of sodium carbonate and, further, with a saturated aqueous solution of sodium chloride once again, followed by drying o~er anh~drous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (carrier 50 g, developillg solvent : ethyl acetate-hexane=1:3) to afford 6~-phthalimido-b-desoxyfumagillol (0.99 g: yield 68%).
NMR spectrum (~ value; CDCQ3): 1.27(lH,m), 1.32(3H,s), 1.65 to 2.70(7H,m), 1.67(3H,s), 1.73(3H,m), 2.58(1H,d,4Hz), 2.99(1H,d,4Hz), 3.33(3H,s), 4.36(1H,m), 4.71(lH,t,lOHz), 5.23(lH,m), 7.73(2H,m), 7.83(2H,m).
Reference Example 10 6~-Amino-6-6-desoxyfumagillol 6~-Phthalimido-6-desoxyfumagillol (2.0 ~) was dissolved in methanol (40 ml), to which was added hydrazine-hydrate (1.4 g), and the mixture was stirred for 20 minutes. The solvent was distilled off under reduced pressure, and the residue was subjected to azeotropic distillation with ethanol to remove the excess amount of hydrazine-hydrate. The residue was dissolved in water (20 ml), to which was added acetic acid (1.5 ml), and the mixture was stirred overnight.
Resulting precipitates were filtered of~. To the filtrate was added conc. ammoniacal water (4 ml), then the product was extracted with chloroform. The extract solution was dried over anhydrous magnesium sulfate, then the sol~ent was distilled off under reduced pressure. The residue was purified by means of a silica g~l column chromatography (carrier lO0 g, developing solvent: chloroform-methanol-conc.
ammoniacal water=30:1:0.03) to afford 6~-amino-6-desoxyfumagillol (0.9 g: yield 40%).
NMR spectrum (~ value; CDCQ3): 1.17(1HIm), 1.29(3H,s), 1.50 to 1.95(4H,m), 1.66(3H,s), 1.79(3H,m), 2.27(1H,m), 2.37(1H,m), 2.52(1H,d,4Hz), 2.55(1H,t,6Hz), 2.90(1H,m), 2.92(1H,d,4Hz), 3.47(1H,dd,9Hz,llHz), ~ ~ 2 !~ J ~3 ;~
-- so 3.S6(3H,s), 5.22(lH,m).
Reference Example 11 6~-Hexylamino-6-desoxy~umagillol 6~-~mino-6-desoxyfumagillol (3.0 ~), hexanal (1.4 ml) and acetic acid (l.S ml) were dissolved in methanol (60 ml). ~o the solution was added sodium cyanoborohydride (0.67 g). The mixture was stirred for one hour, and the resulting reaction mixture was diluted with ethyl acetate (100 ml), followed by washing with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodi.um chloride. The resultant was dried over anhydrous ~agnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of a silica gel column chromatography (carrier 150 g, developing solvent: chloroform-methanol-conc. ammoniacal water=30:1:0.03) to afford 6~-hexylamino-6-desoxyfumagillol (2.35 g: yield 60%).
NMR spectrum (~ value; CDC~3): 0.89(3H,m), 1.10 to 2.35(12H,m), 1.66(3H,s), 1.74(3H,m), 2.51(1H,d,4Hz), 2.92(1H,d,4Hz), 3.50(3H,s), 3.69(1I~,dd,9Hz,llHz), 5.22(lH,m).
Reference Example 12 2-(1,2-epoxy-1,5-dimethyl-~-hexenyl)-3-methoxy-1-methylthiomethyl-4-oxo-1-cyclohexanol 6-Oxo-6-desoxyfumagillol (870 mg) was dissolved in DMF (2 ml), to which was added thiomethoxide (652 mg).
The mixture was stirred for 30 minutes, followed by addition of water thereto to suspend the reaction. The product was extracted with isopropylether. The extract solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, which was then dried over anh~drous magnesium sulfate. The solvent was distilled off under - 51 - ~ ~2~3~
reduced pressure. The residue was purified by means of a silica gel column chromatography (carrier 50 g, developing solvent: eth~l acetate-hexane=1:2) to afford 2-~1,2-epoxy-1,5-dimethyl-~-hexenyl)-3-methoxy-4-oxo-1-methylthiomethyl-l-cyclohexanol (693 mg: yield 70%).
NMR spectrum ~ value; CDC~3): 1~46(3H,s), 1.67~3H,s), 1.75(3H,s), 1.88(1H,m), 2.05 to 2.60(4H,m), 2.20(3H,s), 2.30(1H,d,12Hz), 2.80(1H,m), 2.91(1H,d,13Hz), 2.99(1H,d,13Hz), 3.30(1H,t,6Hz), 3.41(3H,s), 3.~8(1H,d,12Hz), 5.20(1H,m).
Example la 2 (1,2-Epoxy-1,5-dimethyl-4~hexenyl)-3-methoxy-1-bromomethyl 1,4-cyclohexanediol To a solution of fumagillol (230 mg) in ethanol (2 ml) was added a 5~ aqueous solution of hydrobromic acid (1 ml), and the mixture was s~irred ~ox one hour at room temperatures. The reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, followed by concentration under reduced pressure. The concentrate was purified by means of a silica gel column chromatography (carrier 10 g, developing solvent: hexane-ethyl acetate=7:3) to afford 2-(1,2-epoxy-1,5-dimethyl~4--hexenyl)-3-methoxy-1-bromome~hyl-1,4-cyclohexanediol (242 mg: yield 80~) as a colorless oily product.
NM~ spectrum (~ value; CDCR3): 1.40(1H,m), 1.50(3H,s), 1.67(3H,s), 1.74(3H,s), 1.5 to 2.6(7H,m) 3.00(1H,t,6Hz), 3.2 to 3.4(1H,m), 3.35(3H,s), 3.49(1H,d,lOHz), 3.70(1H,d,lOHz), 3.90(1H,br g~, 4.22(lH,m), 5.19(lH,m).
Example lb 2-(1,2-Epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-iodomethyl-1,4-cyclohexanediol Sodium iodide (398 mg) and sodium acetate (36.3 mg) were dissolved in a mixture of acetic acid (0.5 ml) and propionic acid (1 ml). To the solution was added, under ice-cooling, ~umagillol (500 mg). The mixture was stirred for 20 minutes, which was then poured into a conc. ammoniacal water (l0 ml) to suspend the reaction. The product was e~tracted with ethyl acetate. The extract solution was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (carrier 20 g, developing solvent: ethyl acetate-he~ane=1:2), followed by crystallization ~rom isopropylether to afford 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-iodomethyl-1,4-cyclohexanol (667 mg: yield 92%) as colorless crystals, m.p. 86 to 88C.
NMR spectrum (S value; CDC~3): 1.48(1H,m), 1.51(3H,s), 1.67(3H,s), 1.75(3H,s), 1.70 to 2.55(6H,m), 3.01(1H,t,7Hz), 3.26(1H,m), 3.35(3H,s), 3.50(1H,d,lOHz), 3.57(1H,d,lOHz), 4.20(1H,m), 5.19(lH,m).
Bxample lc 4-O-(Chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-l-chloromethyl-l~4-cyclohexanedi To a solution of O-(chloroacetylcarbamoyl)-fumagillol (100 mg) in methanoI (2 ml) was added 0.4N
hydrochloric acid (1 ml), which was stirred for one hour at room temperatures. Resulting precipitates were collected by filtration and recrystallized from methanol-water to afford 4-O-(chloroacetylcarbamoyl)~2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1,4-cyclohexanediol (96 mg, yield 90%) as colorless crystals.
NMR spectrum (~ ~alue; CDC~3): 1.43(1H,m), 1.50(3H,s), 1.74(3H,s), 1.5 to 2.6(6H,m), 1.95(1H,t,6Hz), 3.30(1~,m), 3.32(3H,s), 3.49(1H,d,llHx), 3.87(1H,d,llHz), 4.12(1H,br s), 4.52(2H,s), 5.18(1H,m), 5.45(1H,m), 8.06(1H,br s).
Example 2 4-O-(Acryloylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1,4-cyclohexanediol To a solution of 2-(1,2-epoxy-l,S-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1,4-cyclohexanediol (418 mg) in dichloromethane (5 ml) was added dropwise acryloylisocyanate (300 mg). The mixture was stirred for 30 minutes at room temperatures. To the reaction mixture was added water, which was subjected to extraction with ethyl acetate. The extract solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (carrier 20 g, developing solvent: hexane-ethyl acetate=4:1) to afford 4-O-(acryloylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-l-chloromethyl-lr4-cyclohexanedi (200 mg, yield 38%) as colorless crystals.
NMR spectrum (~ value; CDCR3): 1.50(3H,s3, 1.66(3H,s), 1.74(3H,s), 1.35 to 2.6(7H,m), 2.96(1H,t,7Hz), 3.30(1H,m), 3.33(3H,s), 3.48(1H,d,llHz), 3.87(1H,d,llXz), 4.12(1H,br s), 5.18(lH,m),5.45(lH,m), 5.91(lH,dd,llHz,2Hz), 6.55(1H,dd,17Hz,2Hz), 7.08(1H,dd,17Hz,l].Hz), 7.64(1H,br s ) .
Example 3 4-O-(methacryloylcarbamoyl)-2-~1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1,4-cyclohexanediol - 54 - 2~2l~3 Likewise in Example 2, a mixture of 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1,4-cyclohaxanediol (1.13 g) and methacryloylisocyanate (800 mg) was stirred for 30 minut~s at room temperatures. 'rhe reaction mixtu.re was puri~ied by means o~ ~ silica gel column chromatography (carrier 50 g, developing solvent:hexane-ethyl acetate=3:1) to a~ford 4-O-(methacryloylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3 methoxy-1-chloromethyl-1,4-cyclohexanediol (520 mg, yield 34~) as colorless crystals.
NMR spectrum (~ value; CDC~3) : 1.51(3H,s), 1.66(3H,s), 1.74(3H,s), 2.02(3H,s), 1.2 to 2.6(7H,m), 2.97(1H,t,6Hz), 3.3 to 3.4(1H,m), 3/34(3H,s), 3.54(1H,d,llHz), 3.86(1H,d,llHz), 4.11(1H,br s), 5.18(1H,m), 5.50(1H,d,3Hz), 5.60(1H,d,2Hz), 5.78(1H,s), 7.81(1H~S)-Example 4 4-0-(3-Chloro-2-methyl-propionylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1,4-cyclohexanediol Likewise in Example 2, 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-l-chloromethyl-ll4~cyclohexanedi (1.13 g) and methacryloylisocyanate (800 mg) were stirred for 30 minutes at room temperatures. The resultant product was purified by means of a silica gel column chromatography (carrier 50 g, developing solvent:hexane-ethyl acetate=4:1) to a~ford 4-0-(3-chloro-2-methyl-propionylcarbamoyl)~2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1,4-cyclo-- hexanediol (281 mg, yield 17%) as colorless crystals.
NMR spectrum (~ value;CDCQ3): 1.31(3H,d,7Hz), 1.50(3H,s), 1.75(3H,s?, 1.2 to 2.55(7H,m), 2.97(1H,t,6Hz), 3.33(3H,s), 3.49(1H,d,llHz), 3.87(lH,d,llHz), 3.25 to 4.3(4H,m), 4.11(lH,br s), 2 ~
- ss -5.18(lH,m), 5.45(lH,d,3Hz), 7.82(lH,br s).
Example 5 4-O-Phenylthioace-tylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-phenylthiomethyl 1,4-cyclohexanediol To a solution o~ O-chloroacetylcarbamoylfu~lagillol (122 mg) in ~MF (2 ml) was add~d thiophenol.sodium salt (400 mg), and the mixture was stirred for 30 minutes at room temperatures. The reaction mixture was diluted with ethyl acetate, and the organic lay~r was washed with water and a saturated aqueous saline solution, followed by drying over magnesium sulfate. The solvent was distilled off under reduced pressure, then the residue was puri~ied by means o~ a silica gel column chromatography (carrier 10 ~, developing solvent:hexane-ethyl acetate=5:1) to afford 4-O-(phenylthioacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-phenylthiomethyl-1,4-cyclohexanediol (181 mg, yield 99%) as colorless powder.
NMR spectrum ~ value; CDCQ3): 1.45(3H,s), 1.65(3H,s), 1.72(3H,s), 1.2 to 2.5(7H,m), 2.96(lH,t,7Hz), 3.31(3H,s), 3.39(3H,m), 3.98(1H,d,14Hz), 4.00(1H,br s), 4.08(1H,d,14Hz), 5.18(1H,br s,7Hz), 5.44(1H,br s), 7.1 to 7.5~10H,m), 8.29(1H,br s).
Example 6 4-O-(l-naphthylthioacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-(1-naphthylthiomethyl)-1,4-cyclohexanediol Likewise in Example 5, O-chloroacetylcarbamoyl ~umagillol (129 mg) and 1-naphthylthiol.sodium salt (302 mg) were stirred for 10 minutes at room temperatures, and the resultant was puri~ied by means 2 ~
of a silica gel column chromatography (carrier 10 ~, developin~ solvent:hexane-ethyl acetate=4:1) to afford 4-O-(1-naphthylthioacetylcarbamoyl)-2-(1,2-epoxy-l,S-dimethyl-4~hexenyl)-3-methoxy-1-(1-naphthylthiomethyl)-1,4-cyclohexanediol (207 mg, yi~ld 94%) as colorless po~,7der.
NMR spectrum (~ value; CDC~3): 1.46(3H,s), 1.64(3H,s), 1.72(3H,s), 1.2 to 1.95(4H,m), 2.05 to 2.55(3~,m), 2.96(1H,t,6Hz), 3.11(3H,s), 3.2 to3.4(1H,m), 3.40(1H,d,13Hz), 3.43(1H,d,13Hæ),4.02(1~,d,15Hz), 4.05(1H,br s), 4.13(1H,d,15Hz), 5.17(1H,m), 5.42(1H,m), 7.3 to 7.95(13H,m), 8.44(2H,m).
Example 7 4-0-(8-Quinolylthioacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-(8-quinolylthiomethyl)-1,4-cyclohexanediol Likew~se in Example 5, O-chloroacetylcarbamoyl fumagillol (119 mg) and 8-mercaptoquinoline.sodium salt (357 mg) were stirred for 30 minutes at room temperatures.
The resultant product was purified by means of a silica gel column chromatography (carrier 10 g, developing solvent:hexane-ethyl acetate=7:3) to af~ord 4-0-(8-quinolylthioacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)~3-methoxy-1-(8-quinolylthiomethyl)-1,4-cy-clohexanediol (181 mg, yield 89~) as colorless powder.
NMR spectrum (~ value; CDC~3): 1.48(3H,~), 1.82(3H,br s), 1.93(3H,br s), 1.2 to 2.6(7H,m), 2.97(1H,m), 3.39(3H,s), 3.3 to 3.6(3H,m), 3.93(1H,d,15Hz), 4.01(1H,d,15Hz), 4.28(1H,br s), 5.12(lH,m), 5.56(lH,m), 7.4 to 7.95(8H,m), 8.1 to 8.25(2H,m), 8.86(1H,m), 9.I7(1H,dd,4Hz,2Hz), 10.94(1H,br s).
~ ~ ~ f~
Example 8 4-O-carbamoyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-(~-quinolylthiomethyl~1,4-cyclohexanediol Likewise in Example 5, O-carbamo~l fumagillol (200 mg) and ~-mercaptoquinoline.sodium salt (300 mg) were stirred for one hou~ at room temperatures. The resultant product was purified by means of a silica gel column chromatography (carrier 10 g, developing solvent: hexane - ethyl acetate=1:2) to afford 4-O-carbamoyl-2-(1,2-epoxy-1,5-dimethyl--4-hexenyl)-3-meth-oxy-1-(8-~uinol~lthiomethyl)-1,4-cyclohexanediol (233 mg, yield 78~) as colorless powder.
NMR spectrum (~ value; CDC~3): 1.48(3H,s), 1.62(6H,br s), 1.2 to 2.6(7H,m), 2.95(1H,m), 3.39(3H,s), 3.3 to 3.4(2H,m), 3.47(1H,d,12Hz), 4.26(1H,m)t 4.79(1H,br s), 4.85(2H,br s), 5.15(1H,br s), 5.39(1H,m), 7.4 to 7.5(2H,m), 7.55 to 7.8(2H,m), 8.18(1H,d,8Hz), 8.95(1H,dd,4Hz,2Hz).
Example 9 4-O-Carbamoyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol To a solution of O-chloroacetylcarbamoyl fumagillol (209 mg) in ethanol (2 ml) was added a 15%
aqueous solution of methanethiol.sodium salt (500 ~1), and the mixture was stirred ror one hour at room temperatures. The reaction mixture was concentrated, to which was added ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (carrier 10 g, developing solvent: hexane-ethyl acetate=2:1) to afford 4-O-carbamoyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-l-methylthiomethyl-1,4-cyclohexanediol (136 mg:
yield 70%) as colorless powder.
NMR spectrum (~ value; CDC~3~: 1.48(3H,s), 1.67(3H,s), 1.74(3I-I,s), 1.2 to l.9(5H,m), 2.18(1H,m), 2.21(3H,s), 2.46(]H,m), 2.85(1H,d,14Hz), 2.96(1H~m), 2.98(1H,d,14Hz), 3.31(1H,m), 3.33(3H,s), 4.71(2H,br s), 5.20(lH,m), 5.33(1~I,m).
Example 10 2-(1,2-Epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol Fumagillol (3.00 g) was dissolved in DMF (6 ml), to which was added thiomethoxide (2.23 g). The mixture was stirred for 30 minutes, to which was added water to suspend the reaction. The product was extracted with isopropylether. The extract solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, then the residue was purified by means of a silica gel column chromatography (carrier 150 g, developing solvent :
ethyl acetate - hexane = 1:2), followed by recrystallization from hexane to afford 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (2.43 g : yield 69~) as colorless powder, m.p. 52 to 53C.
NMR spectrum (~ value; CDC~3): 1.45(3H,s), 1.55(1H,m), 1.66(3H,s), 1.74(3H,s), 1.65 to 1.90(4H,m), 2.08 to 2.55(2H,m), 2.80 to 3.02(3H,m), 3.30(1H,m), 3.35(3H,s), 4.22(1H,m), 5.19(lH,m).
[ ~26 57 5o (c 0.20, CHC~3) Elemental analysis : Cl7H30O4S
Calcd. C:61.78%, H:9.15%, Found C:61.66%, H:9.30~.
Example 11 59 2~2~¢~; ~
4-O-Acetyl-2-(1,2-epox~-:L,5-dimethyl-4-hexenyl)-3-methoxy-l-methylthiomethyl-1,4-cyclohexanediol In dichloromethane (5 ml) was dissolved 2-(1,2-epoxy-1,5-dimethyl~4-hexenyl)-3-methoxy-l~methylth-iomethyl-1,4-cyclohexanediol (620 mg). To the solution were added dimethylaminopyridi.ne (252 m~) and acetic anhydride (0.20 ml), then the mixture was stirred for one hollr. The reaction mixt~re was diluted with ethyl acetate (70 ml), which was washed with water, a 10%
aqueous solution o~ citric acid and a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (carrier 30 g, lS developing solvent: ethyl acetate - hexane = 1:2), ~ollowed by crystallizatio~ ~rom hexane to af~ord 4-O-acetyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-l-methylthiomethyl-1,4-cyclohexanediol t730 mg: yield 100%) as colorless crystals, m.p. 73 to 74C.
NMR spectrum (~ value; CDC~3): 1.48(3H,s), 1.66(3H,s), 1.74(3H,s), 1.60 to 1.90(4H,m), 2.00 to 2.55(3H,m), 2.12(3H,s), 2.21(3H,s), 2.85 to 3.00(3H,m), 3.29(3H,s), 3.34(1H,m), 5.20(1H,m), 5.47(1H,m).
[a]D6-71~8 (c 0.22, CHC~3).
Elemental analysis : C1~H32O5S
Calcd. C:61.26%, H:8.66%, Found C:61.35%, H:8.86.
Example 12 4-O-(Chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol In dichloromethane (lS ml) was dissolved 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-5-methoxy-l-methylth-iomethyl-1,4-cyclohexanediol (1.50 g). To the solution was added dropwise, under ice-cooling, chloroacetyl - 60 - ~ ~2'~3~
isocyanate (0.46 ml). The mixture was stirred ~or 20 minutes, which was diluted with ethyl acetate (60 ml) and washed with a saturated aqueous solution of sodium hydrogencarbonate and a sa~urated aqueous saline sol~ltlon, Eollowed by drying over anhydrous ma~nesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by mearls of a silica gel column chromato~raphy (carrier 75 g, developing solvent : ethyl acetate - hexane = 1:2), followed by crystallization from ether-hexane to afford 4-O-(chloroacety]carbamoyl)-2~(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (1.70 g: yield 83%) as colorless crystals, m.p. 101 to 102C.
NMR spectrum (~ value; CDC~3): 1.46(3H,s), 1.66(3H,s), 1.74(3H,s), 1.60 to 1.92~4H,m), 2.05 to 2.55(3H,m), 2.21(3H,s), 2.84(1H,d,13Hz), 2.93(lH,t,7Hz), 2.99(lH,d,13Hz), 3.32(3H,s), 3.34(lH,m), ~.51(2H,s), 5.19(1~,m), 5.45(lH,m).
[~26 81 5 (c 0.20,CHCQ3).
Elemental analysis for CZoH32No6scl :
Calcd. C:53.38%, H:7.17%, N:3.11%
Found C:53.34%, H:7.14~, N:3.03%
Example 13 4-O-(Chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5 dimethyl-4-hexenyl)-3-methoxy-1-dimethylsulfoniomethyl-1,4-cyclohexanediol iodide In acetonitrile (2 ml) was dissolved 4~0-(chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-h-exenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (500 mg~. To the solution was added methyl iodide ~0.82 ml), and the mixture was stirred for 8 hours. The solvent was distilled off under reduced pressure. The residue was pulverized by the addition of ether to afford 4-O-(N-chloroacetyl-- 61 ~
carbamoyl)-2-(1,2-epoxy-1,5-dimethyl-~-hexenyl)-3-methoxy-l-dimethylsulfoniomethyl-1,4-cyclohexanediol iodide (701 m~: yield 100~) as pale yellow powder.
NMR sp~ctrum (6 vallle; CD~OD): 1.47(3H,s), 1.69(3H,s), 1.75(3H,s), 1.65 to 1.95(4H,m), 2.10 to 2.60(3H,m), 3.01(3~1,s), 3.07(3H,s), 3.12tlH,t,6Hz), 3.46(1H,m), 3.70(1H,d,13Hz), 4.03(2H,s), 4.05(lH,d,13Hz), 5.24(lH,m), 5.48(lH,m).
[~]D6-49.o (c 0.20, CHCQ3).
Elemental analysis for C2lH35NO6SCII.4H2O:
Calcd. C:37.99%, N:2.11%, Found C:38.07~, N:2.16%
Example 14 4-O-acetyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-l-dimethyls~llfoniomethyl-1,4-cyclohexanediol iodide Likewise in Example 13, 4-acetoxy-2-~(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-dimethyl-sulfoniomethyl~l,4-cyclohexanediol iodide (558 mg:
yield 82%) ~as obtained as pale yellow powder from 4-O-acetyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-l-methylthiomethyl-1,4-cyclohexanediol (490 mg).
NMR spectrum (~ value; CD30~): 1.46(3H,s), 1.69(3H,s), 1.75(3H,s), 1.65 to 1.85(4H,m), 2.05 to 2.60(3H,m), 2.08(3H,s), 2.98(3H,s), 3.06(3H,s), 3.12(1H,t,6Hz), 3.30(3H,s), 3.44(1H,m), 3.74(1H,d,13Hz), 4.03(1H,d,13Hz), 5.24(1H,m), 5.51(lH,m).
[a]D6-58.6 (c 0.22, CHC~3).
Example 15 4-O-(Chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-ethylmethylsulfoniomethyl-1,4-cyclohexanediol iodide Likewise in Example 13, 4-O-(chloroac~tyl-~ .J~
carbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-ethylmethylsulfoniomethyl-1,4-cyclohexanediol iodide (59 mg: yield 44~) was obtained as pale yellow powder from 4-O-(chloroacetylcarbamoyl)-2-(1,2-epoxy-S 1,S-dimethyl-4-hexenyl)-3-methoxy-1-meth~lthiomethyl-1,4-cyclohexanediol (150 mg).
NMR spectrum (~ value; CD30D): 1.35 tol.5Q(6H,m), 1.69(3H,s), 1.75(3H,s), 1.65 to 1.95(4H,m), 2.05 to 2.60(3H,m), 2.97(1.5H,s), 3.06(1.SH,s), 3.12(1H,m), 4.03(2H,m), 4.45(1H,m), 5.25(lH,m), 5.45(lH,m).
[~]D6-62.7 (c 0.22, CHCR3).
Eleme~tal analysis for C22H37NO6SClI :
Calcd. C:43.61%, H:6.15~, N:2.31%, Found C:43.83%, H:6.19%, N:2.39~.
Example 16 4-O-(N-chloroacetylcarbamoyl)-2-(1,2-epoxy-l,S-dimethyl-4-hexenyl)-3-methoxy-1-benzylmethylsulfoniomethyl-1,4-cyclohexanediol bromide Likewise in Example 13, 4-O-(N-chloroacetyl-carbamoyl)-2 (1,2-epoxy-l,S-dimethyl-4-hexenyl)-3-methoxy-l-benzylmethylsulfoniomethyl-1,4-cycl-ohexanediol bromide (152 mg: yield 73~) was obtained as colorless powder from 4-O-~N-chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5 dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (150 mg).
NMR spectrum (~ value; CD30D): 1.42(3H,m), 1.68(3H,s), 1.65 to 2.00(4H,m), 2.10 to 2.60(3H,m), 2.82(1.5H,s), 3.00(1.5H,s), 3.12(1H,m), 3.30 to 3.75(8H,m), 4.03(lH,m), 4.45 to 5.05(4~,m), 5.25(lH,m), 5.45(1H,m).
[a]D6-43.0 (c 0.22, CHC~3).
Elemental analysis for C27H39NO6SBrCl-2-5H2O :
Calcd. C:48.69%, H:6.66%, N:2.10~
Found C:48.66%, H:6.35%, N:2.29%.
- 63 - 2~ J
Example 17 ~-O-(Chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-(2-propinyl)-methylsulfoniomet}lyl-1,4-cyclohexanediol bromide L.ikewise in Example 13, ~rom 4~0-(chloroacQtyl-carbamoyl)~2-(1,2-epoxy-l,S-dimethyl-4-hexenyl)-3-methoxy-l-methylthiomethyl-1,4-cyclohexanediol (150 mg) was obtained 4~0-O-~chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy~ 2-p~opinyl)methylsulfoniomethyl-1,4-cyclohexanediol bromide (97 mg: yield 51%) as pale yellow powder.
NMR spectrum (~ value; CD30D): 1.40(1.5H,s), 1.45(1.5H,s), 1.68(3H,s), 1.74(3H,s), 1.65 to 2.00(4H,m), 2.10 to 2.60(3H,m), 2.90 to 3.90(9H,m), 4.18(2H,m), 4.44(lH,s), 5.25(lH,m), 5.45(lH,m).
~a]26-43.0 (c 0.20, CHC~3).
Elemental analysis for C23H35NO6SBrCl:
Calcd. C:48.55%, H:6.20%, N:2.46%, Found C:48.48% H:6.21%, N:2.59%.
Example 18 4-O-(l-Naphthyl)carbamoyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-5-methoxy-1-methylthiomethyl-1,4-cyclohexanediol - 25 Likewise in Example 12, 4-O-(l-naphthyl)carbamoyl~
2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-5-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (378 mg: yield 83%) was obtained as colorless powder from 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthi-omethyl-1,4-cyclohexanediol (300 mg).
NMR spectrum (~ value; CDC3): 1.45(3H,br s), 1.67(3H,s), 1.75(3H,s), 1.65 to 2.00(4H,m), 2.05 to 2.55(3HIm), 2.17(3HIbr s), 2.75 to 3.05(2H,m), 3-32(lH~m)~ 3-37(3H,m), 5.21(1H,m), 5.51(lH,m), 7.44 to 8.00(7H,m) [~]~6-85.5O (c 0.22, CHC~3).
2 ~2'~
Example 19 ~-O-(l-Naphthyl)carbamoyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-di.me-thylsulfoniomethyl-1,4-cyclohexanediol iodide Likewise in Example l3, from 4-O-(l-naphthyl)-carbamoyl-2-(1,2-epoxy-1,5-dimethyl-~-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (150 mg) was obtained 4-O-(1 naphthyl)carbamoyl-2-(1,2-epoxy-1,S-dimethyl-4-hexenyl) 3-methoxy-1-dimethyl-sulfoniomethyl-1,4-cyclohexanediol iodide (177 mg:
yield g2%) as pale yellow powder.
NMR spectrum (~ value; CD30D): 1.44(3H,br s), 1.69(3H,s~, 1.76(3H,s), 1.70 to 2.00(4H,m), 2.10 to 2.60(3H,m), 2.98(3H,s), 3.06(3H,s), 3.12(1~1,m), 3.39(3H,s), 3.45(2H,m), 4.02(1~,m), 5.27(lH,m), 5.45(lH,m).
[~26 51 0 (C O . 22, CHC~3).
Elemental analysis for C29H4ONO5SI :
Calcd. C:54.29~, H:6.28%, N:2.18~, Found C:54.17%, H:6.35~, N:2.08%
Example 20 4-0-(2-benzothiazoyl)thioacetylcarbamoyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-dimethylsulfoniomethyl-1,4-cyclohexanediol iodide In methanol (1 ml) was dissolved 4-O-(chloro-ace~ylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-dimethylsulfoniome'hyl-1,4-cyclohexanediol iodide (200 mg). To the solution was added 2-mercaptobenzothiazol.sodium salt (127 mg), and the mixture was stirred for 30 minutes. The reaction mixture was diluted with ethyl acetate (70 ml), then washed with water, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution,followed by drying over anhydrous - 65 - 2 ~
magnesium sulfate. The solvent was distilled off under reduced pressure, then the residue was purified by means of a sillca gel column chromatography tcarrier 10 g, developing solvent: chloroform-methanol=10:1) to afford ~-0-(2~benzothiazoyl)thioacetylcarbamoyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-metho~y l-dimethyl-sulfoniomethyl-1,4-cyclohexanediol iodide (65.8 mg:
yield 26%) as colorless powder.
NMR spectrum (~ value: CD3QD): 1.48(3H,s), 1.6~(3H~s), 1.73(3H,s), 1.65 to 1.90(5H,m), 2.00 to 2.55(2H,m), 2.96(1H,m), 3.06(3H,s), 3.20(1H,m), 3.27(3H,s), 3.31(3H,s), 3.81(1H,d,14Hz), 4.40 to 4.70(3H,m), 5.i4(lH,m), 5.42(lH,m), 7.25 to 7.50(2H,m), 7.15(1H,d,7H2), 7.89(1H,d,8Hz).
[a]26-4.7 (c 0.10, CHCQ3).
E~ample 21 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-phenylthiomethyl-1,4-cyclohexanediol To methanol (5 ml) was added, under ice-cooling, 60% sodium hydride (213 mg), and the mixture was stirred for 5 minutes at room temperatures, to which was then added thiophenol (0.55 ml), followed by stirring for 15 hours. To the resultant mixture was added fumagillol (500 mg), which was stirred for 30 minutes, followed by adding water to suspend the reaction. The product was extracted with ethyl acetate, and the extract solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure r and the residue was purified by means of a silica gel column chromatography (carrier 25 g, developing solven~: ethyl acetate-hexane = 1:2), followed by crystallization from isopropylether to afford 2-(1,2-epoxy-1,5-dimethyl-4-- 66 - 2~2~30~
hexenyl)-3-methoxy-l-phenylthiomethyl-ll4-cyclohexanediol (660 mg: yield 95%) as colorless crystals, m.p. 94 to 96C.
NMR spectrum (~ vallle; CDCR3): 1.45(3H,s), 1.45 to 1.95(4H,m), 1.66(3H,s), 1.73(3~1,s), 2.05 to 2.55(3~1,m), 2.99(1H,m), 3.20 to 3.45(3H,m), 3.35(3H,s), 4.22(1H,m), 5.19(lH,m), 7.10 to 7.45(5~1,m).
[~]26_4l 4 (c 0.21, CHC~3) Elemental analysis for C22H32O4S :
Calcd. C:67.31~, H:8.22~, Found C:67.36%, H:8.30%.
Example 22 4~0-(Chloroacety].carbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-phenylthiomethyl-1,4-cyclohexanediol LiXewise in Example 12, from 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-l-phenylthiomethyl-l~4 cyclohexanediol (450 mg) was obtained 4-O-(chloro-acetylcarbamoyl)-2~ 2-epoxy-l r 5-dimethyl-4-hexenyl)-3-methoxy-1-phenylthiomethyl-1,4-cyclohexanediol (541 mg: yield 92%) as colorless powder.
NMR spectrum (~ value; CDCQ3): 1.46(3H,s), 1.66(3H,s), 1.73(3X,s), 1.50 to 1.92(4H,m~, 2.00 to 2.55(3H,m), 2.96(1H,t,6Hz), 3.23(3H,s), 3.38(2H,s), 3.25 to 3.50(1H,m), 4.52(2H,s), 5.18(1H,m), 5.45(1H,m), 7.15 to 7.45(5H,m).
[~]26-56.0 (c 0.21, CHCQ3).
Elemental analysis for Cz5H34NO6SCl:
Calcd. C:58.64%, H: 6.69%, N:2.74%, Found C:58.41%, H:6.69%, N:2.79%
Example 23 4-O-(Chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-phenylsulfinylmethyl-1,4-cyclohexanediol - 67 - 2n~
In dlchloromethane (2 ml) was dissolved 4 O-(chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-h-exenyl)-3-methoxy-1-phenylthiomethyl-1,4-cyclohexanediol (200 m~). To t:he solution was added, under ice-cooling, m-chloroperbenzoic acid (80.9 mg), and the mixture was stirred for 30 minutes. The reaction mixture was diluted with ethyl acetate ~70 ml), which was washed with a saturated aqueous solution o~ sodium hydrogencarbonate and a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was then purified by means of a silica gel column chromatography (carrier 10 g, developing solvent: ethyl acetate - hexane = 1:2) to afford 4-O-(chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-phenylsulfinylmethyl-l,4-cyclohexanediol (175 mg: yield 85%) as colorless powder.
NMR spectrum (~ value; CDC~3): 1.49(3H,s), 1.65(3H,s), 1.73(3H,s), 1.55 to 2.55(7H,m), 2.98(1H,t,6Hz), 3.31(1H,d,14Hz), 3.25 to 3.45(5H,m), 4.47(2H,s), 5.05 to 5.2S(lH,m), 5.49(1H,m), 7.50 to 7.70(5H,m)-[~]D6-88.6 (c 0.22, CHC~3).
Elemental analysis for C25H34NO7SC~Ø5H2O:
Calcd. C:55.91%, H:6.57%, N:2.61%, Found C:55.18%, H:6.39%, N:2.68%.
Example 24 4-O-(chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-iodomethyl-1,4-cyclohexanediol Likewise in Example 12, from 2-(1,2-epoxy-lr5 dimethyl-4-hexenyl)-3-methoxy-1-iodomethyl-1,4-cyclohexanediol (200 mg) was obtained 4-O-(N-chloro-acetylcarbamoyl)-2-(1,2~epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-iodomethyl-1,4-cyclohexanediol (222 mg:
- 68 - 2~
yield 86%) as colorless crystals, m.p. 140 to 141C.
NMR spectrum (~ value; CDC~3): 1.45 to 2.00(4~,m), 1.53(3H,s), 1.67(4H,s), 1.75(3H,s), 2.10 to 2.55(3H,m), 3.30(1H,m), 3.32(3H,s), 3.51(1H,d,lO~Iz), 3.53(1H,d,lOHz), 4.51(2H,s), 5.18(1H,m), 5~44(lH,m).
[a]D6~74.5 (c 0.22, CHC~3).
Elemental analysis for Cl9H29NO6ClI:
Calcd. C:43.07~, H:5.52%, Ns2.64%, Found C:42.81%, H:5.45%, N:2.65%.
Example 25 4-O-Acetyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-iodomethyl-3-methoxy-1,4-cyclohexanediol In dichloromethane (5 ml) was dissolved 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-iodomethyl-1,4-cyclohexanediol (2.08 g). To the solution were added dimethylaminopyridine (0.74 g) and acetic anhydride (0.58 ml)~ The mixture was stirred for 30 minutes. The reaction mixture was diluted with ethyl acetate (50 ml), which was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, then the solvent was purified by means of a silica gel column chromatography (carrier lO0 g, developing solvent:
ethyl acetate - hexane = 1:3) to afford 4-O-acetyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-iodomethyl-3-methoxy-1,4-cyclohexanediol (2.19 g: yield 95%) as a colorless oily product.
NMR spectrum (~ value; CDCR3): 1.52(3H,s), 1.53(1H,m), 1.66(3H,s), 1.74(3H,s), 1.65 to 2.00(4H,m), 2.12(3H,s), 2.10 to 2.60(3H,m), 2.98(1H,t,6Hz), 3.26(1H,m), 3.55(2H,s), 5.18(1H,m), 5.44(1H,m).
[a]26-66.5 (c 0.20, CHC~3).
~ 69 - 2 Example 26 4-(N'-Chloroacetylureido)-2-(1,2-epoxy-1,5-dimethyl-4-he~enyl)-3-methoxy-l-methylthiomethyl-1-cyclohexanol In methanol (5 ml) were dissolved 2-(1,2-epoxy-1,5-dimethyl-~-hexenyl)-3 methoxy-1-methylthiomethyl-4-oxy-l-cyclohexanol (200 mg) and ammonium acetate (487 mg). To the solution was added sodium cyanoborohydride (40 mg), and the mixture was stiLred ~or one hour. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate (50 ml).
The solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in dichloromethane (2 ml). To the solution was added dropwise at 0C
chloroacetylisocyanate (0.08 ml). The mixture was stirred for 15 minutes at the same temperature, which was then diluted with ethyl acetate (50 ml). The solution was washed with a saturated aqueous solution o~ sodium hydrogencarbonate and a saturated a~ueous solution of sodium chloride, followed by drying over anhydrous magnesium sulfate. The solvent was distilled of under reduced pressure, and the residue was purified by means of a silica gel column chromatography (carrier 25 g, developing solvent: ethyl acetate hexane = 1:3) to afford 4-(N~-chloroacetylureido)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-l-cyclohexanol (129 mg: yield 45%) as colorless powder.
NMR spectrum (~ ~alue; CDC~3): 1.48(3H,s), 1.40 to 2.55(7H,m), 1.66(3H,s), 1.73(3H,s), 2.20(3H,s), 2.85(1H,d,13Hz), 2.g9(1H,t,6Hz), 2.96(1H,d,13Hz), 3.32(3H,s), 3.40(1H,dd,4Hz,12Hz), 4.14(2H,s), 4.51(lH,m), 5.18(lH,m).
~ 70 - 2~ 3 ~i~
[~]D 60.8 (c 0.21,CHC~3).
Elemental analysis for C20H33N2O5C1Ø2H2O:
Calcd. C:53.07~, H:7.44%, N:6.19~, Found C:52.81%, H:7.42~, N:6.57~.
s Example 27 4 (N'-chloroacetylureido)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-dimethylsulfoniomethyl-1-cyclohexanol iodide Likewise in Example 13, from 4-(N'-chloro-acetylureido)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-l-methylthiomethyl-1-cyclohexanol (132 mg) was obtained 4-(N'-chloroacetylureido)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-]nethoxy-1-dimethylsulfoniomethyl-1-cyclohexanol. iodide (130 mg: yield 100%) as a pale yellow powdexy product.
NMR spectrum (~ value, CD30D): 1.40 to2.55(7H,m), 1-47(3H~s)~ 1-69(3H,s), 1.75t3H,s), 2.97(3H,s), 3.04(3H,s), 3.14(1H,t,6Hz), 3.31(3H,s), 3.51(1H,m), 3.67(1H,d,13Hz), 3.83(2H,s), 4.03(1H,d,13Hz), 4.41(1H,m), 5.24(1H,m).
Elemental analysis for C2lH38N2O5SClI.4H2O:
Calcd. C:38~04%, N:4.23%, Found C:37.91%, N:4.41%.
Example 28 4-O-(~hloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylsulfinylmethyl-1,4-cyclohexanediol Likewise in Example 23, from 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (156 mg) was obtained 4-O-(chloro-acetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylsul~inylmethyl-1,4-cyclohexanediol (156 mg: yield 100%) as colorless powder.
NMR spectrum (~ ~alue; CDC~3): 1.45(1.5H,s), - 71 - 2~2~3~
1.50(1.5H,s), 1.67(3H,s), 1.74(3H,5), 1.70 to 2.60(7H,m), 2.68(1.5H,s), 2.72(1.5H,s), 2.95(1H,t,6Hz), 3 15 to 3.28(3H,m), 3.31(1.5H,s), 3.37(1.5H,s), 4.48(2H,s), 5.20(lH,m), 5.46(lH,m).
~ 26 _90 o (c 0.20,CHC~3)-Elemqntal analysis ~or C20H32NO7SCl-H2O:
Calcd. C:49.63~, H:7.0~, N:2.89~, Found C:49.49%, H:6.73%, N:2.89%.
Example 29 4-O-(Chloroacetylcarbamoyl)-2-(1,2-epoxy-1.5-di.methyl-4-hexenyl)-3-methoxy-1-methylsulfonylmethyl-1,~-cyclohexanediol 4-O~(chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexellyl)-3-methoxy-l-methylsulfinylmethy].-1,4-cyclohexanediol (300 mg) was dissolved in dichloromethane (2 ml), to which was added, under ice-cooling, m-chloroperbenzoic acid (179 mg), and the mixture was stirred for one hour. The reaction mixture was diluted with ethyl acetate (70 ml), which was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by a silica gel column chromatography (carrier 15 g, developing solvent: ethyl acetate - hexane 2:1) to afford 4-O-(chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-h exenyl)-3-methoxy-1-phenylsulfonylmethyl-1 r 4~ ~
cyclohexanediol (91 mg: yield 30%) as colorless powder.
NMR spectrum (~ value: CDCQ3): 1.47(3H,s), 1.67(3H,s), 1.75(3H,s), 1.70 to 2.60(7H,m), 3.00(1H,m) 3.05(3H,s), 3.25 to 3.45(2H,m), 3.33(3H,s), 3.80(1H,d,15Hz), 4.47(2H,s), 5.17(1H,m), 5.46(1H,m).
[~]D -96.5 (c 0.20, CHCQ3).
Elemental analysis for C20H32NO8~C1Ø7H2O:
- 72 - 2~
Calcd. C:48.57%, H:6.81%, N:2.83%, Found C:48.62%, H:6.57%, N:2.86%.
Example 30 2--(1,2-Epoxy-1,5-dimethyl-4-hexenyl)-3 methoxy-l-(4 pyridyl)thiomethyl-1,4-cyclohexanediol ~,ilcewise in Example 21, from ~uma~illol (1.00 g) was obtained 2-(1,2-epoxy-1,5-dimethyl)-4-hexenyl)-3-methoxy-1-(4-pyridyl)thiomethyl-1,4-cyclohexanediol (1.15 g: yield 81%) as a pale yellow oily product.
NMR spectrum (~ value; CDC~3): 1.47(3H,s), 1.50 to 1.90(4Hrm), 1.67(3H,s), 1.74(3H,s), 2.05 to 2.60(3H,m), 3.04(1H,t,6Hz), 3.2~(1H,d,13Hz), 3,29(1H,m), 3.35(3H,s), 3.50(1H,d,13Hz), 4.23(1H,m), 5.20(1H,m), 7.19(2H,m), 8.38(2H,m).
Example 31 4-O-(Chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4~hexenyl)-1-(4-pyridyl)thiomethyl-3~me-thoxy-1,4-cyclohexanediol Likewise in Example 12, from 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-(4-pyridyl)thiomethyl-1,4-cyclohexanediol (911 mg) was obtained 4-O-(chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5 dimethyl-4-h-exenyl)-1-~4-pyridyl)thiomethyl-3-methoxy-1,4-cyclohexanediol (1.02 g: yield 83%) as colorless powder.
NMR spectrum (~ value; CDC~3): 1.46(3H,s), 1.55 to 2.00(4H,m), 1.66(3H,s), 1.74(3H,s), 2.05 to 2.60(3H,m), 2.99(1H,t,6Hz), 3.25 to 3.40(2H,m), 3.33(3H,s), ; 3.50(1H,d,12Hz), 4.51(2H,s), 5.18(1H,m), 5.47(1H,m), 7.21(2H,m), 8.42(2H,m).
Elemental analysis for C24H33N2O6SC1Ø5H2O:
Calcd. C:55.22%, H:6.55%, N:5.37%, Found C:55.07%, H:6.19%, N:5.59%.
2 ~ 3 Example 32 4-O-(Chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-metho~y-1-(N-methyl-4-pyridinio)-thiomethyl-1,4-c~clohexanedi.ol iodide S Likewise in Example 13, ~rom 4-O-(chloroacetyl-carbamoyl) 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(4-pyridyl)thiomethyl-3-methoxy-1,4-cyclohexanediol (165 m~) was obtained 4-O-(chloroacetylcarbamoyl)-2~(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-(N-methyl-4-pyridinio)thiomethyl-1,4-cyclohexanediol iodide (212 mg: yield 100%) as pale yellow powder.
NMR spectrum (~ value; C~30D): 1.49(3H,s), 1.55 to 2.60(7H,m), 1.68(3H,s), 1.70(3H,s), 3.13(1H,m), 3.20 to 3.60(2H,m), 3.99(1H,m), 4.Q3(2H,s), 4-23(3H~s)~
5.25(3H,s), 5A47(1H,m), 7.99(2H,m), 8.52(2H,m).
Example 33 2-(1,2-Epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-l-(pyrimidin-2-yl)thiomethyl-1,4-cyclohexanediol Likewise in Example 21, ~rom ~umagillol (500 mg) was obtained 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-l-(pyrimidin-2-yl)thiomethyl-l~4-cyclohexanediol (426 mg: yield 61~) as an oily product.
NMR spectrum (~ value; CDC~3): 1.40 to 2.10(4H,m), 1.60(6H,s), 1.71(3H,s), 2.65(1H,d,14Hz)), 2.70 to 2.90(3H,m), 3.53(3H,s), 4.10 to 4.32(2H,m), 4.16(1H,d,15Hz), 5.23(1H,m), 6.92(1H,t,5Hz), 8.43(2H,d,SHz) Example 34 4-O-(Chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-(pyrimidin-2-yl)thiomethyl-1,4-cyclohexanediol Likewise in Example 12, ~rom 2-(1,2-epoxy-1,5-- 35 dimethyl-4-hexenyl)-1-(pyrimidin-2-yl)thiomethyl-3-methoxy-1,4-cyclohexanediol (300 mg) was obtained 4-O-2 ~ ,i ,,3 (chloroacetylcarbamo~1)-2-(1,2-epoxy-l,S-dimethyl-4-h-exenyl)-3-me~hoxy-1--(pyrimidin-2-yl)thiomethyl-1,4-cyclohexanediol (344 mg: yield 88%) as pale yellow powder.
NM~ spectrlm~ (~ value; CDCQ3): 1.57(3H,s), 1.5S to 2.05(4~1,m), 1.60(3H,s), 1.71(3~1,s), 2.67(1H,d,lS~Iz), 2.75 to 2.95(3H,m), 3.51(3H,m), 4.10(lH,d,15Hz), 4.26(1H,dd,lHz,llHz), 4.45(3H,s), 5.23(1H,m), 5.52(1H,m), 6.95(2H,t,SEIz), 8.49(1H,d,SHz).
Example 35 2-(1,2-Epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-ethylthiomethyl-1,4-cyclohexanediol Likewise in Example 21, from fumagillol (1.00 g), was obtained 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-l-ethylthiomethyl-1,4-cyclohexanediol (991 mg:
yield 81%) as a pale yellow product.
NMR spectrum (~ value; CDCQ3) 1.27(3H,t,7Hz), 1.46(3H,s), l.SO(lH,m), 1.67(3H,s), 1.74(3H,s), 1.60 to 1.90(3H,m), 2.05 to 2.5X(3H,m), 2.61(2H,q,7Hz), 2.80 to 3.00(3H,m), 3.35(3H,s), 4.22(1H,m), 5.20(1H,m).
Example 36 4-O-(Chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-ethylthiomethyl-1,4-cyclohexanediol Likewise in Example 12, from 2--(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-ethylthiomethyl-3-methoxy-1,4-cyclohexanediol (300 mg) was obtained 4-O-(chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5 dimethyl-4-h-exenyl)-3-methoxy-1-e~hylthiomethyl-1,4-cyclohexanediol (385 mg: yield 95%) as colorless powder.
NMR spectrum (~ value; CDCQ3): 1.29(3H,t,7Hz), 1.48(3H,s), 1.60(1H,m), 1.66(3H,s), 1.74(3H,s), 1.60 to 1.95(3H,m), 2.05 to 2.60(3H,m), 2.62(2H,q,7Hz), 2.84(1H,d,13Hz), 2.93(1H,m), 3.01(1H,d,13Hz), - 75 - ~ ~ L~
3.32(3H,s), 3.35(1H,m), 4.52(2H,s), 5.19(1H,m), .44(1H,m)-Example 37 2-(1,2-Epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-benzylthiomethyl-1,4-cyclohexanediol Likewise in Example 21, from ~umagillol (S00 mg) was obtained 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-benzylthiomethyl-1,4-cyclohexanediol (652 mg:
yield 90~) as a colorless oi:ly product.
NMR spectrum (~ value; CDC~3): 1.38(3H,s), 1.48(1H,m), 1.66(3H,s), 1.74(3H,s), 1.55 to 1.90(3H,m), 2.05 to 2.55(3H,m), 2.75 to 3.00(3H,m), 3.30(lH,m), 3.33(3H,s), 3.74(lH,d,12Hz), 3.80(1H,d,12Hz), 5.19(lH,m), 7.15 to 7.40(5H,m).
Elemental Analysis for C23H34O4SØ32O:
Calcd. C:67.05%, H:8.45%, Found C:67.03%, H:8.54~.
Example 38 4-O-(Chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-benzylthiomethyl~1,4-cyclohexanediol Likewise in Example 12, from 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-benzylthiomethyl-3-methoxy-1,4-cyclohexanediol (461 mg) was obtained 4-O-(chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-h-exenyl)-3-methoxy-1-benzylthiomethyl-1,4 cyclohexanediol (544 mg: yield 91%) as colorless powder.
NMR spectrum (~ value; CDC~3): 1.40t3H,s), 1.45 to 1.90(4H,m), 1.65(3H,s), 1.73(3H,s), 2.05 to 2.60(3H,m), 2.77(lH,d,13Hz), 2.88(lH,m), 2.93(lH,d,13Hz), 4.50(3H,s), 3.76(1H,d,13Hz), 3.80(1H,d,13Hz), 4.50(2H,s), 5.17(1H,m), 5.42(1H,m), 7.20 to 7.40(5H,m).
- 76 - 2~
Example 39 2-(1,2-Epoxy-1,5-dimethyl-~-hexenyl)-3-methoxy-1-allylthiomethyl-1,4-cyclohexanediol Likewise in Example 21, from fumagillol (500 mg) was obtained 2-(1,2-epoxy-l,S-dimethyl-4-hexenyl)-3-methoxy-1-allylthiomethyl-1,~-cyclohexanediol ~555 mg:
yield 88%) as a colorless oily product.
NMR spectrllm (~ value; CDC~3): 1.45(3H,s), 1.52(1H,m), 1.66(3H,s), 1.7~(3H,s), 1.60 to 1.95(3H,m), 2.05 to 2.55(3H,m), 2.83(2H,s), 2.95(1H,t,6Hz), 3.19(2H,d,7Hz), 3.30(1H,m), 3.34(3H,s), 4.22(1H,m), S.05 to 5.25(3H,m), 5.57 to 5.92(lH,m).
Elemental Analysis for ClgH~2O4S:
Calcd. C:64.01%, H:9.05%, Found C:63.71~, H:9.23%
Example 40 4-O-(Chloroacetylcarbamoyl)-2-(1,2-epoxy~1,5-dimethyl-4-hexenyl)-3-methoxy-1-allylthiomethyl-1,4-cyclohexanediol Likewise in Example 12, from 2-(1,2-epoxy-l,S-dimethyl-4-hexenyl)-l-allylthiomethyl-3-methoxy-1,4-cyclohexanediol (374 mg) was obtained 4-O-(chloroacetylcarbamoyl)-2-(1,2-epoxy-l,S-dimethyl-4-h-exenyl)-3-methoxy-1-allylthiomethyl-1,4-cyclohexanediol (441 mg: yield 88%) as colorless powder.
NMR spectrum (~ value; CDC~3): 1.47(3H,s), 1.55 to 1.95(4H,m), 1.66(3H,s), 1.74(3H,s), 2.05 to 2.55(3H,m), 2.80(lH,d,13Hz), 2.91(lH,d,13Hz), 2.92(lH,m), 3.20(3H,d,7Hz), 3.32(3H,s), 3.35(1H,m), 4.51(2H,s), S.lO to 5.25(3H,m), 5.44(lH,m), 5.72 to 7.93(lH,m).
Example 41 4-O-(N-Chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)~3-methoxy-1-allylmethyl-sulfoniomethyl-1,4-cyclohexanediol bromide _ 77 - ~2~13~6 Likewise in Example 13, from 4-O-(N-chloroacetyl-carbamo~l) 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-l-methylthiomethyl-1,4-cyclohexanediol (120 mg) was ohtained 4-O-(N-chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-allylmethyl-s~llfoniomethyl-1,4--cyclohexanediol bromide (126 mg:
yield 82~) as colorless powder.
NMR spectrum (~ value; CD30D): 1.35 to 1.50(6H,m), 1.69(3H,s), 1.75(3H,s), 1.60 to 2.60(7H,m), 2.90(1.5H,s), 3.02(1.5H,s), 2.95 to 3.70(6H,m), 4.18(2H,m), 4.44(lH,m), 5.15 to 6.15(5H,m).
Example 42 4-O-Phenoxycarbonyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthionmethyl-1,4-cyclohexanediol In dichloromethane (2 ml) were dissolved 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylth-iomethyl-1,4-cyclohexanediol (200 mg) and dimethylaminopyridine (115 mg). To the solution was added, under ice-cooling, phenyl chloroformate (95 ~1), and the mixture was stirred for 16 hours. The reaction mixture was diluted with ethyl acetate (70 ml), washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (carrier 10 g, developing solvent: ethyl acetate - hexane = 1:4) to afford 4-O-phenoxycarbonyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (222mg: yield 81%) as a colorless oily product.
NMR spectrum (~ value, CDC~3): 1.48(3H,s~, 1.67(3H,s), 1.74(3H,s), 1.65 to a.95(4H,m), 2.10 to - 78 ~ 2~
2.55(3H,m), 2.2)(3H,s), 2.87(1H,d,13Hz), 2 95(1H,t,7Hz), 2.96(1H,d,13Hz), 3.35(3H,s), 3.35(1H,m), 5.20(1H,m~, 5.39(1H,m), 7.15 to 7.45(5H,m).
Example 43 4-O-Phenoxycarbonyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-dimetllylsuloniomethyl-1,4-cyclohexanediol iodide Likew.ise in Example 13, from 4-O-phenoxycarbonyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-c~clohexanediol tl45 mg) was obtained 4-O-phenoxycarbonyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-dimethylsulfoniomethyl-1,4-cyclohexanediol iodide (165 mg: yield 87~) as pale yellow powder.
NMR spectrum (~ value; CD30D): 1.49(3H,s), 1.69(3H,s), 1.76(3H,s), ]..65 to 2.05(4H,m), 2.10 to 2-60(3H~m), 3.01(3H,5), 2.99(3H,s), 3.07(3H,s), 3.13(1H,t,6Hz), 3.38(3H,s), 3.52(1H,dd,3Hz,12Hz), 3.67(1H,d,14Hz), 4.04(1H,14Hz), 4.86(2H,s), 5.26(1H,m), 7.12 to 7.~7(5H,m).
Example 44 4-O-Benzoyl-2-(1,2-epoxy~1,5-dim~thyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol Likewise in Example 42, from 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3~methoxy-l-methylthiomethyl-1,4-cyclohexanediol (100 mg) was obtained 4-O-benzoyl 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (91 mg: yield 69%) as a colorless oily product.
NMR spectrum (~ value; CDC~3): 1.50(3H,s), 1.66(3H,s), 1.73(3H,s), 1.60 to 2.60(7H,m), 2.24(3H,s), 2.85(1H,d,13Hz), 3.00(1H,t,6Hz), 3.09(1H,d,13Hz), 3.33(3H,s), 3.40(1H,m), 5.19(1H,m), 5.74(1H,m), 7.40 to 7.65(3H,m), 8.08(2H,m).
- 79 - ~ ~2'~3 Example 45 4-O-Tosyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-l-methylthiomethyl-1,4-cyclohexanediol Likewise in Example 42, from 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-:l-methylthiomethyl-1,4-cyclohexanediol t200 mg) was obtained 4~0-tosyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl) 3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (57 mg: yield 19%) as a colorless oily product.
NMR spectrum (~ value; CDC~3): 1.40(3H,s), 1.64(3H,s), 1.72(3H,s), 1.60 to 1.95(4H,m), 2.05 to 2.50(3H,m), 2.13(3H,s), 2.45(3H,m), 2.85(1H,d,13Hz), 2.86(1H,t,6Hz), 2.93(1H,d,13Hz), 3.06(3H,s), 3.20(lH,m), 5.02(lH,m), 5.16(lH,m), 7.34(2H,d,8Hz), 7.84(2H,d,8Hz).
Example 46 4-O-Mesyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-iodomethyl-1,4-cyclohexanediol Likewise Example 42, from 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-iodomethyl-1,4-cyclohexanediol (300 mg) was obtained 4-O-mesyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-iodomethyl-1,4-cyclohexanediol (314 mg: yield 88%) as a calorless oily product.
NMR spectrum t~ value; CDC~3): 1.51(3H,s), 1.60(1H,m), 1.66(3H,s), 1.74(3H,s), 1.80 to 2.55(6H,m), 2.95(1H,t,6Hz), 3.11(3Hrs), 3.30(1H,m), 3.38(3H,s), 3.53(lH,d,llHz), 3.56(lH,d,llHz), 5.19(lH,m), 5.22(lH,m).
Example 47 4-O-Mesyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol Li~ewise in Example 10, from 4-O-mesyl-2~(1,2-3 ~3 ~
epoxy-1,5~dimethyl-4~hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (179 mg) was obtained 4-O-mesyl-2-(1,2-epoxy-1,5-dimethyl-4-hexen~l)-3--methoxy-1-methylthiomethyl-1,4-S cyclohexanediol (112 mg: yield 74~) as a colorless oilyproduct.
NM~ spectrum (S value; CDC~): 1.46(3H,s), 1.67(3H,s), 1.74(3H,s), 1.65 to 2.55(7EI,m), 2.20(3H,s), 2.91(3H,m), 3.11(3H,s), 3.34(1H,m), 3.38(3H,s), 5.19(lH,m), 5.24(lH,m).
Example 48 2-(1,2-Epo~y-l,S-dimethyl-4-hexenyl)-3-methoxy-1-(pyrrolidin-1-yl)methyl-1,4-cyclohexanediol N-oxide lS Fumagillol (S00 mg) was dissolved in pyrrolidine (1 ml), and the solution was stirred at 50C overnight.
Excess volume of pyrrolidine was distilled off under reduced pressure to leave 2-(1,2-epoxy-l,S-dimethyl-4-hexenyl)-3-methoxy-1-(pyrrolidi~ yl)methyl-1,4-cyclohexanediol as a crude product. This crude product was dissolved in chloroform (5 ml), to which was added m-chloroperbenzoic acid (458 mg), and the mi.xture was stirred for 30 minutes. The solvent was distilled of~
under reduced pressure, and the residue was purified by means of a silica gel column chromatography (carrier 25 g, developing solvent: chloroform - methanol -am~oniacal water = 15:1:0.1) to obtain 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-(pyrrolidin-1-yl)methyl-1,4-cyclohexanediol N-oxide (554 mg: yield 84%) as colorless powder.
NMR spectrum (~ value; CDC~3): 1.43(1H,d,9Hz), 1.51(3H,s), 1.68(3H,s), 1.71(3H,s), 1.65 to 2.65(6H,m), 2.95(1H,d,13Hz), 3.15 to 3.55(4H,m), 3.48(3H,s), 3.88(3H,m), 4.28(lH,m), 5.24(lH,m).
[~]D6-20.so (c 0.21,CHCQ3).
Elemental Analysis for C20H35NO5.H2O:
- 81 - 2~2~3~,~
Calcd. C:61.99%, H:9.62%, N:3.61%, Found C:62.02%, H:9.60~, N:3.60%.
Example 49 S 4-O-Chloroacetylcarbamoyl~2-(1,2-epoxy-1,5-dimethyl-4-hexellyl)-3-methoxy-1-(pyrrolidin-1-yl)methyl-1,4-cyclohexanediol N-oxide Likew.ise in Exampl.e 12, from 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methox~-1-(pyrrolidin-1-yl)methyl-1,4-cyclohexanediol N-oxide (350 mg) was obtained 4-O-chloroacetylcarbamoyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-pyrrolidin-1-yl)methyl-1,4-cyclohexanediol N-oxide (74 mg: yield 16%) as colorless powder.
NMR spectrum (~ value; CDC~3): 1.47t3H,s), 1.20 to 2.80(11H,m), 1.68(3H,s), 1.72(3H,s), 3.20 to 4.10(7H,m), 3.42(3H,s), 4.49(2H,s), 5.22(1H,m), 5.48(lH,m).
~]26_4l o (c 0.20, CHC~3)-Elemental Analysis for C23H37O7Cl.H2O:
Calcd. C:54.49%, H:7.75%, Found C:54.17%, ~:7.33%.
Example 50 2-(1,2-Epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-(N-methylpyrrolidin-l-ylio)methyl-1,4-cyclohexanediol iodide Fumagillol (500 mg) was dissolved in pyrrolidine (1 ml), and the solution was stirred at 50C overnight.
Excess volume of pyrrolidine was distilled off under reduced pressure to leave 2~(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-(pyrrolidin-1-yl~methyl-1,4-cyclohexanediol as a crude product. This crude product was dissolved in dichloromethane (5 ml), to which was added methyl iodide (1.1 ml), and the mixture W2S
stirred overnight. The solvent was distilled off under - 82 ~
reduced pressure, and the residue was puri~ied by means of a silica gel column chromatography ~developing solvent: chloroform-methanol-ammoniacal water =
10:1:0.1), followed by pulverizincJ with ether to obtain 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy~ N-methylpyrrolidin-l-ylio)methyl-1,4-cyclohexanediol iodide (446 mg: yield 50~) as colorless powder.
NMR spectrum (~ value; CD30D): 1.45(3H,s), 1.68(3H,s), 1.75(3H,s), 1.65 to 2.60(11H,m), 3.05 to 3.45(2H,m), 3.23(3H,s), 3.34(3H,s), 3.55 to 3.90(4H,m), 3.62(1H,d,14Hz), 3.92(1H,d,14Hz), 4.25(1H,m), 5.25(lH,m).
Example 51 4-O-Chloroacetylcarbamoyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-(N-methylpyrrolidin-l-ylio)methyl-1,4-cyclohexanediol iodide Likewise in Example 12, from 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-(N-methylpyrrolidin-1-ylio)methyl-1,4-cyclohexanediol iodide (200 mg), was obtained 4-O-chloroacetylcarbamoyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-(N-methylpyrrolidin-l-ylio)methyl-1,4-cyclohexanediol iodide (76 mg: yield 30%) as colorless powder.
NMR spectrum (~ value; CD30D): 1.46(3H,s), 1.68(3H,s), 1.-75(3H,s), 1.80 to 2.60(11H,m), 3.14(1H,t,6Hz), 3.25(3H,s), 3.34(3H,s), 3.46(1H,m), 3.60 to 3.90(4H,m), 3.69(1H,d,14Hz)`, 3.95(1H,d,14Hz), 3.46(2H,s), 5.24(1H,m), 5.46(1H,m).
3~
Example 52 4~-(Morpholino)carbonyloxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl cyclohexanol Likewise in Example 10, from 4~-(morpholino)- ~
carbonyloxy~6-epifumagillol (110 mg) was obtained 4~-O-(morpholino)carbonyl-2-(1,2-epoxy-1,5-dimethyl-4-hexen-- g3 ~
yl)-3-methoxy-1-methylthiomethylcyclohexanol (81 mg:
yield 64%) as a colorless oily product.
NMR spectrum (~ value; CDC~3): 1.47(3H,s), 1.66t3H,s), 1.74(3H,s), 1.50 to 2.45(7H,m), 2.83(1H,d,13Hz), 2.94(1H,d,13Hæ), 3.05(1~,t,6Hz), 3.35 to 3.80(~H,m), 4.69(1~l,m), 5.~2(lM,m).
Example 53 4~-Hexylamino-2~(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-l~methylthiomethylcyclohexanol Likewise in Example lO, fxom 6~-hexylamino~6-desoxyfumagillol (110 mg) was obtained 4~ hexylamino-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethylcyclohexanol (110 mg: yield 88%) as a colorless oily product.
NMR spectrum (~ value; CDCR3): 0.88(3H,m), 1.20 to 1.90(12H,m), 1.48(3H,s), 1.65(3H,s), 1.73(3H,s), 2.17(3H,s), 2.32(2H,m), 2.50(2H,m), 2.71(lH,m), 2.78(1H,d,13Hz), 2.91(1H,d,13Hz), 3.03(1H,m), 3.40(2H,m), 3.48(3H,s), 5.23(lH,m).
Example 54 l-(~-Bromobenzyl)methylsulfoniomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol bromide In chloroform (0.5 ml) were dissolved 2-(1,2-epoxy-1,5-dimethyl-4-hexenylj-3-methoxy-l-methylth-iomethyl-1,4-cyclohexanediol (200 mg) and 4-bromobenzyl bromide (756 mg). To the solution was added silver bromide (11.4 mg), and the mixture was stirred for 28 hours. Insolubles were filtered off, and the solvent was distilled off. The residue was pulverized by~the addition of ether. The resul~ing powder was dissolved in methanol (2 ml). Insolubles were fil~ered off, then the solvent was distilled off under reduced pressure.
The residue was pulverized by the addition of ether to ~ ~ ~ L~ 3 ~ ~
give 1-(4-bromobenzyl)methylsulfoniomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol bromide (176 mg: yield 50%) as colorless powder.
NMR spectrum (~ value; CD30D): 1.43(3H,s), 1.68(3H,s), 1.55 to 1.90(4H,m), ~.10 to 2.55(3H,m), 2.~2(1.5,s), 3.10(1H,t,6}~z), 3.27(1H,m), 3.33(1.5H,s), 3.35(1.5H,s), 3.54(1H,m), 3.86 to 4.12(1H,m), 4.24(lH,m), 4.50 to 4.92(2H,m), 5.24(lH,m), 7.48(2H,m), 7.69(2H,m).
Example 55 1-(4-Chlorobenzyl)methylsulfoniomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol bromide Likewise in Example 54, 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (200 mg) wa~ allowed to react with 4-chlorobenzyl bromide (1.24 g) to yive 1-(4-chlorobenzyl)methylsulfoniometh~1-2~(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol bromide (228 mg: yield 70~) as colorless powder.
NMR spectrum (~ value; CD30D): 1.43(3H,s), 1.68(3H,s), 1.75(3H,s), 1.55 to 1.90(4H,m), 2.10 to 2.55(3H,m), 2.82(1.5H,s), 2.99(1.5H,s), 3.09(1Htt,6Hz), 3.27(1H,m), 3.33(1.5H,s), 3.35(1.5H,s), 3.54(1H,m), 3.88 to 4.11(1H,m), 4.24(1H,m), 4.50(0.5H,d,18~z), 4.71(1H,s), 4.91(0.5H,d,18Hz), 5.23(1H,m), 7.53(3H,m).
Example 56 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(4-fluorobenzyl)methylsulfoniomethyl-3-methoxy-1,4-cyclohexanediol bromide Likewise in Example 54, 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclo-hexanediol (200 mg) was allowed to react with 4-r~
fluorobenzyl bromide (1.14 g) to give 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(4-fluorobenzyl)methyl-sulfoniomethyl-3-methoxy-1,4-cyclohexanediol bromide t223 mg: yield 71%) as colorless powder.
NMR spectrum (~ value; CD30D): 1.'~3(3H,s), 1.68(3H,s), 1.7~(3H,s), 1.55 to 1.90(4H,m), 2.10 to 2.55(3H,m), 2.80(1.5}l,s), 2.98(1.5H,s), 3.10(1H,t,6Hz), 3.25(1H,m), 3.33(1.5H,s), 3.35(1.5H,s), 3.53(1H,m), 3.85 to 4.12(1H,m), 4.24(1H,m), 4.60(0.5H,d,17Hz), 4.71(lH,s), 4.92(0.5H,d,17Hz), 5.23(lH,m), 7.25(2H,m), 7.59(2H,m).
Example 57 2-(1,2-Epoxy-1,5-dimethyl-4--hexenyl)-3-methoxy-1-(4-methylbenzyl)methylsulfoniomethyl-1,4-cyclohexanediol bromide Likewise in Example 54, 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclo-hexanediol (200 mg) was ~llowed to react with 4-methylbenzyl bromide (1.12 g) to give 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)~3-methoxy-1-(4-methylbenzyl)-methylsulfoniomethyl-1,4-cyclohexanediol bromide (198 mg: yield 56~) as colorless powder.
NMR spectrum (~ value; CD30D): 1.42(1,5H,s), 1.44(1.5H,s),1.68(3H,s), 1.74(3H,s), 1.55 to 1.90(4H,m), 2.39(3H,s), 2.10 to 2.55(3H,m), ; 2.75(1.5H,s), 2.94(1.5H,s), 3.08(1H,t,6Hz), 3.27(1H,m), 3.33(1.5H,s), 3.35(1.5H,s), 3.49(1H,d,12Hz), 3.80 to 4.10(1H,m), 4.24(1H,m), 4.61(0.5H,d,13Hz), 4.66(1H,s), 4.87(0.5H,d,13Hz), 5.23(lH,m), 7.37(4H,m).
Example 58 1-(3-Bromobenzyl)methylsulfoniomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol bromide Likewise in Example 54, 2-(1,2-epoxy-1,5-dimethyl-2 ~ 7, ~
4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclo-hexanediol (200 mg) was allowed to react with 3-bromobenzyl bromide (1.51 g) to ~ive 1-(3-bromobenzyl)-methylsulfoniomethyl-2-(l,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol bromide (184 m~:
yield 52%) as colorless powder.
NMR spectrum (~ value; CD30D): 1.44(3H,s), 1.68(3H,s), 1.7~t3H,s), 1.55 to 1.90(4H,m), 2.10 to 2.55(3H,m), 2.83(1.5H,s), 3.10(1H,t,6Hz), 3.25(1H,m), 3.33(1.5H,s), 3.35(1.5H,s), 3.53(1H,m), 3.8S to 4.12(1H,m), 4.24(1H,m), 4.60(0.5H,d,17Hz), 4.69(1H,s), 4.83(0.5H,d,17Hz), 5.23(1H,m), 7.35 to 7.85(4H,m).
Example 59 1-(2-Bromobenzyl)methylsulfoniomethyl-2-(1,2-epoxy-1,5-d.imethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol bromide Likewise in Example 54, 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclo-hexanediol (200 mg) was allowed to react with 2-bromobenzyl bromi~e (1.51 g) to give 1-(2-bromobenzyl)-methylsulfoniomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol bromide (29 mg:
yield 8%) as colorless powder.
NMR spectrum (~ value; CD30D): 1.46(3H,s), 1.69(3H,s), 1.75(3H,s), 1.55 to 1.95(4H,m), 2.10 to 2.55(3H,m), 2.90(1.5H,s), 3.08(1.5H,s), 3.11(1H,t,6Hz), 3.25(1H,m), 3.31(1.5H,s), 3.35(1.5H,s), 3.63 to 4.05(2H,m), 4.24(1H,m), 4.66(1H,~), 4.78(0.5H,d,13Hz), 5.18(0.5H,d,13Hz), 5.23(lH,m), 7.15 to 7.83(4H,m).
Example 60 1-(4-Bromobenzyl)methylsulfoniomethyl-4-(N-chloroacetylcarbamoyloxy)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol bromide To a solution of 1-(2-bromobenzyl)methyl-2 ~
sulfoniomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol bromide (150 mg) in dichloromethane (2 ml) was added dropwise, under ice-cooling, chloroacetylisoc~anate (40 ml), then the mixture was stirred ~or 30 minutes. To the reaction mixture was added water ~o suspend the reaction. The product was ex~racted with ethyl acetate. The or~anic layer was washed with a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (carrier 10 g, developing solvent : chloroform-methanol=20:1) to give 1-(4-bromobenzyl)methylsulfoniomethyl-4-(N-lS chloroacetylcarbamoyloxy)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol bromide (80 mg: yield 44%).
NMR spectrum (~ value; CD30D): 1.43(3H,s), 1.68(3H,s), 1.74(3H,s), 1.50 to 2.00(4H,m), 2.10 to 2.55(3H,m), 2.86(1.5H,s), 3.01(1.5H,s), 3.10(1~,t,6Hz), 3.34(1.5H,s), 3.37(1.5H,s), 3.45(1H,m), 3.57(1H,m), 3.gO to 4.15(1H,m), 4.43(2H,s), 4.60(0.5H,d,13Hz), 4.73(1H,s), 4.91(0.5H,d,13Hz), 5.23(1H,m), 5.45(1H,m), 7.49(2H,m), 7.69(2H,m).
[~]D5-43.50 (c 0.20, CHCQ3).
Example 61 4-(N-Chloroacetylcarbamoyloxy)-1-(4-chlorobenzyl)methylsulfoniomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)~3-methoxycyclohexanol bromide Likewise in Example 60, from 1-(4-chlorobenzyl)-methylsulfoniomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol (183 mg) was obtained 4-(N-chloroacetylcarbamoyloxy)-1~(4-chlorobenzyl)methylsulfoniomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol bromide (123 ~ ~ 2 ~
- ~8 -mg: yield 55%) as colorless powder.
NMR spectrum (~ value; CD30D): 1.43(3H,s), 1.68(3H,s), 1.74(3H,s), 1.60 to 1.95(4H,m), 2.10 to 2.55(3H,m), 2.85(1.5H,s), 3.01(1.5H,s), 3.09(1~1,t,6Hz), 3.33(1.5H,s), 3.34(1.5H,s), 3.45(1H,m), 3.58~1H,m), 3 90 to 4.18(lH,m), ~.43(lH,m), ~.44(1H,s), 4.66 to 4.98(2H,m), 5.23(lH,m), 5.46(lH,m), 7.55(4H,m).
[a]D4-~5.2 (c 0.22, CHC~3).
Example 62 4-(N-Chloroacetylcarbamoyloxy)-2-(1,2-epoxy-1,5- , dimethyl-4-hexenyl)-1-(4-fluorobenzyl)-methylsulfoniomethyl-3-methoxycyclohexanol bromide Likewise in Example 60, from 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(4-fluorobenzyl)methyl~
sulfoniomethyl-3-methoxy-1,4-cyclohexanediol (181 mg) was obtained 4-(N-chloroacetylcarbamoyloxy)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl-1-(4-fluorobenzyl)-methylsulfoniomethyl-3-methoxycyclohexanol bromide (118 m~: yield 52%) as colorless powder.
NMR spectrum (~ value; CD30D): 1.43(3H,s), 1.68(3H,s), 1.74(3H,s), 1.50 to 1.95(4H,m), 2.10 to 2.55(3H,ml, 2.84(1.5H,s), 3.00(1.5H,s), 3.10(1H,t,6Hz), 3.33(1.5H,s), 3.35(1.5H,s), 3.45(1.5H,m), 3.58(1H,m), 3.90 to 4.18(lH,m), 4.43(lH,m), 4.44~lH,s), 4.70(0.5H,d,13Hz?, 4.87(1H,s), 4.99(0.5H,d,13Hz), 5.23(lH,m), 5.46(lH,m), 7.26(2H,m), 7.61(2H,m).
[a]24-53.3 (c 0.22, CHC~3).
Example 63 4-(N-Chloroacetylcarbamoyloxy)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl_-3-methoxy-1-(4-methylbenzyl)methylsulfoniomethylcyclohexanol bromide Likewise in Example 60, from 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-(4-methylbenzyl) methylsulfoniomethyl-1,4-cyclohexanediol (165 mg) was 3 ~ ~
obtained 4-(N-chloroacetylcarbamoyloxy)-2-(1,2-epoxy-1,S-dimethyl-4-hexenyl)-3-methoxy-1-(4-methylbenzyl)methylsulEoniomethylcyclohexanol bromide (107 mg: yield 52%) as colorless powder.
NMR spectrum (~ value; CD~OD): 1.42(1.5H,s), 1.~3(1.5H,s), 1.68(3H,s), 1.74(3H,s), l.SO to 1.95(4H,m), 2.39(3H,s), 2.10 to 2.55t3H,m), 2.79(1.5H,s~, 2.97(1.5H,s), 3.09(1H,t,6Hz), 3.32(1.5H,s), 3.35(1.5H,s), 3.45(1H,m),3.52(1H,m), 3.85 to 4.15(1H,m), 4.43(1H,m), 4.44(1H,s), 4.63(0.5H,d,13Hz), 4.69(1H,s), 4.92(0.5H,d,13Hz), 5.22(lH,m), 5.46(1H,m), 7.33(3H,m), 7.43(2H,m).
~]D4-46.40 (c 0.22, CHC~3).
lS Example 64 1-(3-Bromobenzyl)methylsulfoniomethyl-4-(N-chloroacetylcarbamoyloxy)-2-(1,2-epoxy-l,S-dimethyl-4-hexenyl)-3-methox~cyclohexanol bromide Likewise in Example 60, from 2-~1,2-epoxy-1,5-dimethyl 4-hexenyl)-3-methoxy-1-(4-methylbenzyl)-methylsulfoniomethyl-1,4-cyclohexanediol (222 mg) was obtained 1-(3-bromobenzyl)methylsulfoniomethyl-4-(N-chloroacetylcarbamoyloxy)-2-(l~2-epoxy-l~5-dimethyl-4 hexenyl)-3-methoxycyclohexanol bromide (171 mg: yield 64%) as colorless powder.
NMR spectrum (~ value; CD30D): 1.43(3H,s), 1.68(3H,s), 1.73(3H,s), 1.50 to 1.95(4H,m), 2.10 to 2.60(3H,m), 2.87(1.5H,s), 3.01(1.5H,s), 3.11(1H,t,6Hz), 3.32(1.5H~s), 3~34(1.5H,s), 3.45(1H,m), 3.57(1~,m), 3.90 to 4.15(1H,m), 4.64(0.5H,d,lOHz), 4.73(1H,s), 4.92(0.5H,d,lOHz), 5.22(1H,m), 5.46(1~,m), 7.35 to 7 90(4H,m)-[a]D2-38.3 (c 0.20, CHC~3).
Example 65 Separation of stereoisomers of 1-(3-bromobenzyl)methyl-go 2~2~
sulfoniomethyl~4-(N-chloroacetylcarbamoyloxy)-2-(1,2-epoxy-1 r 5-dimethyl-4-hexenyl)-3-methoxycyclohexanol bromide By sub-Jecting 1-(3-bromobenzyl)methylsulfonio-S methyl-4-(N-chloroacetylcarbamOylOxy) 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol bromide (150 my) obtainecl in substantially the same manner as Example 64 to a silica gel column chromatography (carr.ier 10 g, developing solvent: dichloromethane-methanol-water=20:1:0.2), a steroisomer showin~
relatively high Rf value in TLC (developing solvent:
chloroform-methanol=20:1) (isomer ~ : 60 mg) was success~ully separated from a stereoisomer showing relatively low RF value in the same T~C (isomer B : 62 mg), the respective isomers being as colorless powder.
Isomer A :
NMR spectrum (~ value; CD30D): 1.43(3H,s), 1.67(3H,s), 1.73(3H,s), 1.50 to 1.95(4H,m), 2.10 to 2.55(3H,m), 3.01(3H,s), 3.11(1H,m), 3.32(3H,s), 3.43(1H,m), 3.54(1H,d,13Hz), 3.98(1H,d,13Hz), 4.42(2H,s), 4.72(2H,s), 5.21(1H,m), 5.44(1H,m), 7.40 to 7.89(4H,m).
Isomer B :
NMR spectrum (S ~alue; CD30D): 1.43(3H,s), 1.68(3H,s), 1.74(3H,s), 1.50 to 1.95(4H,m), 2.10 to 2.60(3H,m), 2.86(3H,s), 3.11(1H,m), 3.34(3H,s), 3.43(1H,m), 3.53(1H,d,14Hz), 4.12(1H,d,14Hz), 4.43(2H,s~, 4.69(1H,d,13Hz), 4.73(1H,d,21Hz), 4.91(1H,d,13Hz), 5.01(1H,d,21Hz), 5.22(1H,m), 5.47(lH,m), 7.40 to 7.90(4H,m).
Example 66 1-Diallylsulfoniomethyl-2-(1,2 epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol perchlorate To a mixture of 1-allylthiomethyl-2-(1,2-epoxy-1,S-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol - gl -(300 m~) and allyl bromide (0.73 ml) was added silver perchlorate (192 mg) under ice-cooling, which was stirred for 30 minutes at room temperature. Insolubles were filtered off, and the solvent was distilled off S under reduced pressure. The residue was purified by means of a sillca gel column chromatography (carrier 30 g, developing solvent : chloroform-methanol=20:1) to give l-diallylsulfoniomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol perchlorate (160 mg: yield 37~) as colorless powder.
NMR spectrum (~ value; CD30D): 1.45(3H,s), 1.68(3H,s), 1.75(3H,s), 1.60 to 2.60(7H,m), 3.11(1H,t,6Hz), 3.29(1H,m), 3.34(3H,s), 3.90 to 4.35(7H,m), 5.25(lH,m), 5.55 to 6.15(6H,m).
Example 67 l-Diallylsulfoniomethyl-4-(N-chloroacetylcarbamoyloxy)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-cyclohexanol parchloroate To a solution o~ 1-diallylsulfoniomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclo-hexanediol perchlorate (143 mg) in dichloromethane (2 ml) was added dropwise, which was stirred for 30 minutes. To the reaction mixture was added water to suspend the reaction, which was subjected to extraction with ethyl acatate. The organic layer was washed with a saturated aqueous saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (carrier 15 g, developing solvent: chloroform-methanol = 20:1) to give l-diallylsulfoniomethyl-4-(N-chloroacetyl-carbamoyloxy)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol perchlorate (100 mg: yield 56%).
NMR spectrum (~ value; CD30D): 1.45(3H,s), 1.69(3H,s), 1.75(3H,s), 1.55 to 2.60(7H,m), 3.11(1H,m), 2~ 3~
g2 3.34~3H,s), 3.45(1H,m), 3.90 to 4.40(6H,m), 4.43(2H,s), 5.25(lH,m), ~.47(lH,m), 5.55 to 6.20(6H,m).
[a]D4-10.7 (c 0.21, CHC~3).
Elemental Analysis fox C2s~l3sNIoscl2:
Calcd. C:~8.70%, ~1:6.38%, N:2.27%, Found C:48.46~, H:6.67%, N:2.03%.
Example 6~
1-Dibenzylsulfoniomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol perchlorate Likewise in Example 66, from 1-benzylthiomethyl-2-~ epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy~
cyclohexanediol (300 mg) was obtained 1-dibenzyl-sulfoniomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy~ -cyclohexanediol perchlorate (145 mg: yield 33~) as colorless powder.
NMR spectrum (~ value; CD30D): 1.41(3H,s), 1.69(3H,s), 1.75(3H,s), 1.45 to 2.60(7H,m), 3.13(1H,m), 3.22(2H,m), 3.31(3H,s), 4.15(2H,m), 4.47(1H,d,13Hz), 4.71(1H,d,13Hz), 4.76(1H,d,13Hz), 4.98(1H,d,13Hz), 5.23(lH,m), 7.47(10H,m).
Example 69 l-Dibenzylsulfoniomethyl-4-(N-chloromethyl-carbamoyloxy)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol perchlorate Likewise in Example 67, from l-dibenzylsulfonio-methyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol perchlorate (120 mg) was obtained 1-dibenzylsulfoniomethyl-4-(N-chloromethylcarbamoyloxy)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol perchIorate (100 mg:
yield 69%) as colorless powder.
NMR spectrum (~ value; CD30D): 1.41(3H,s), 1.69(3H,s~, 1.74(3H,s), 1.55 to 1.90(4H,m), 2.10 to 2.60(3H,m), 3.04(1H,t,6Hz), 3.30(3H,s), 3.36(2H,m), ~3 ~ "
4.15(1H,d,12Hz~, 4.41(2H,s), 4.55(1H,d,13Hz), 4.74(1H,d,13Hz), 4.80(1H,d,13Hz), 4.98(1H,d,13Hz), 5.22(lH,m), 5.36(lH,m), 7.48(10H,m).
[a]D3-36.4 (c 0.20, CHCl3) Elemental Analysis for C33H~,3NQIoSCl3:
Calcd. C:55.31~, H:6.05~, N:1.95%, Found C:55.66%, H:6.17%, N:2.12%~
Example 70 4-Carbamoyloxy-2-(1 r 2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-dimethylsulfoniomethyl-cyclohexanol iodide Likewise in Example 13, from 4-O-carbamoyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methyl-thiomethyl-1,4-cyclohexanediol (240 mg) was obtained 4-carbamoyloxy-2-(ll2-epoxy-l~5-dimethyl 4-hexenyl)-3-methoxy-1-dimethylsulfoniomethyl-cyclohexanol iodide (282 mg: yield 85%) as colorless powder.
NMR spectrum (~ value; CD30D): 1.46(3H,s), 1.69(3H,s), 1.75(3H,s), 1.65 to 1.90(4H,m), 2.10 to 2.60(3H,m), 3.00(3H,s), 3.06(3H,s), 3.10(1H,t,6Hz), 3.34(3H,s), 3.41(1H,m), 3.73(1H,d,13Hz), 4.04(lH,d,13Hz), 5.25(2H,m).
~26 43 3O (c 0.21, CHC~3)-Elemental Analysis for Cl9H34NO5SI:
Calcd. C:44.27%, H:6.65%, N:2.72%, Found C:44.58~, H:6.87%, N:2.77%.
Example 71 l-Benzylmethylsulfoniomethyl-4-carbamoyloxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenylj-3-methoxycyclohexanol bromide Llkewise in Example 13, from 4-O-carbamoyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methyl-thiomethyl-1,4-cyclohexanediol (200 mg) was ob~ained 1-benzylmethylsulfoniomethyl-4-carbamoyloxy-~-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol bromide (240 mg: yield ~2%) as colorless powder.
NMR spectrum (~ value; CV30D): 1.43(1.5H,s), 1.44(1.5H,s), 1.68(3~1,s), 1.74(3H,s), 1.50 to 1.90(4H,m), 2.10 to 2.60(3H,m), 2.~1(1.5}1,s), S 2.9~(1.5H,s), 3.0~(1E~,t,6Hz), 3.31(1.5H,s), 3.33(1.5H,~), 3.40(1H,m), 3.57(0.5H,d,13Hz), 3.59(0.5H,d,131~z), 4.67(0.SH,d,13Hz), 4.74(lH, B ), 4.95(0.5H~d,13Hz), 5.23(2H,m).
~ ~ ~ 23 _ 36.4 (c 0.20, CHC~ 3 ) .
Elernental Analysis for C25H3aNO5SBr:
Calcd. C:55.14%, H:7.03%, N:2.57~, Found C:55.16~, H:7.32%, N:2.63%.
Example 72 4-(2-Chloroethylcarbamoyloxy)-2-(1,2-epoxy-1,5-dimethyl-~-hexenyl)-3-methoxy-1-methylthiomethylcyclohexanol To a solution of 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-methylthiomethyl-1,4-cyclohexanediol (1.00 g) and dimethylaminopyridine (185 ml) in dichloromethane (10 ml) was added dropwise 2-chloroethylisocyanate (0.52 ml), which was stirred overnight. To the reaction mixture was added water to suspend the reaction, ~hen the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, then the residue was purified by means of a silica gel column chromatography (carrier 50 g, developing solvent :
ethyl acetate - hexane = 1~4) to give 4-(2-chloroethylcarbamoyloxy)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methyl~hiomethylcyclohexanol (912 mg: yield 69~) as colorless powder.
NMR spectrum (~ value; CDC~3): 1.47(3H,s), 1.66(3H,s), 1.74(3H,s), 1.55 to 1.90(4H,m), 2.20(3H,s), 2.05 to 2.60(3H,m), 2.95(3H,m)~ 3.30(1X,m), 3.32(3H,s), s~ ~ ~
3.45 to 3.70(4H,m), 5.20(2H,m).
Example 73 4-(2-Chloroethylcarbamoylox~)-2-~1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-dimethylsulfoniomethylc~clohexanol iodide Likewise in E:xample 13, from 4-(2-chloroethylcarbamoyloxy)-2-(1,2-epoxy-1,5-dime~hyl-4-hexenyl)-3-methoxy-1-methylthiomethylcyclohexanol (150 mg) was obtained 4-(2-chloroethylcarbamoyloxy)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-dimethylsulfoniomethylcyclohexanol iodide (140 mg:
yi.eld 70%) as colorless powder.
NMR spectrum (~ value; CD30D): 1.46(3H,s), 1.69(3H,s), 1.75(3H,s), 1.65 to 1.90(4H,m), 2.I0 to 2.60(3~I,s), 2.99(3~,s)r 3.06(3~,s), 3.10(1Hrm), 3.33(3H,s), 3.35 to 3.65(5H,m), 3.71(1H,d,].4Hz), 4.04(1H,d,14Hz)r 5.25(1Hrm), 5.31(1H,m).
Example 74 1-Benzylmethylsulfoniomethyl-4-chloroacetylcarbamoyloxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3~methoxycyclohexanol tetrafluoroboxate In dichloromethane (1 ml) were dissolved 1-benzylthiomethyl-4-chloroacetylcarbamoyloxy-2~(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol (200 mg) and methyl iodide 10.24 ml).
To the solution was added silver tetrafluoroborater and the mixture was stirred for 8 hours at room temperature. Insolubles were filtered off, and the solvent was distilled off under reduced pressure. The residue was pulverized with ether to give 1-benzylmethylsulfoniomethyl-4-chloroacetylcarbamoyloxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol tetrafluoroborate (73 mg: yield30%) as colorless powder.
2~ J7~3~' - 96 ~
N~R spectrum (~ value; CD30D): 1.41(1.5H,s), 1.42(1.5H,s), (1.68(1.5H,s), 1.75(3H,s), 1.60 to 2.60(7H,m), 2.80(1.5H,s), 3.00(1.5H,s), 3.11(1H,t,6Hz), 3.32(1.5H,s), 3.34(1.5H,s), 3.~5(2H,m), 2.90 to 4.15(1H,m), 4.42(1H,s), 4.43(1~,s), 4.66(0.5H,d,13Hz), 4.70(1~1,s), 4.94(0.5}l,d,13}Iz), 5.22(1H,m), 5.45(1H,m).
[a]D~-23.3 (c 0.21, cHc~e3).
Example 75 1-Benzylmethylsuloniomethyl-4-chloroacetylcarbamoyloxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol tosylate Silver oxide (37 mg) was suspended in ~cetonitrile (1 ml), to which was added p-toluenesulfonic acid .
lS monohydrate (61 ml), and the mixture was stirred for 5 minutes. T~ the resultant was then added 1-benzylmethylsulfoniomethyl-4-chloroacetylcarbamoyloxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol bromide (200 m~). The mixture was stirred for further 30 minutes, then insolubles were filtered o~f. The solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (carrier 4 g, developing solvent : chloroform-methanol = 20:1) to give 1-benzylmethylsulfoniomethyl-4-chloroacetylcarbamoyloxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol tosylate (67 mg: yi21d 29%) as colorless powder.
NMR spectrum (~ value; CD30D): 1.41(1,5H,s), 1.42(1.5H,s), 1.68(1.5H,s), 1.75(3H,s), 2.37(3H,s), 1.60 to 2.60t7H,m), 2.80(1.5H,s), 3.00(1.5H,s), 3.11(1H,t,6Hz), 3.32(1.5H,s), 3.34(1.5H,s), 3.45(2H,m), 3.90 to 4.15(1H,m), 4.42(1H,s), 4.43(1H,s), 4.66(0.5H,d,13Hz), 4.70(1H,s), 4.94(0.5H,d,13Hz), 5.22(1H,m), 5.45(1H,m), 7.23(2H,d,8Hz), 7.72(2H,d,SHz).
~/~2~3~G
Example 76 l-Benzylmethylsulfoniomethyl-4-chloroacetylcarbamoyloxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol hydrogen L-tartrate S Likewise in Example 75, ~rom l-benzylmethyl-sulfoniomethyl-4-chloroacetylcarbamoyloxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol bromide (200 mg) was obtained 1-benzylmethylsulfoniomethyl-4-chloroacetylcarbamoyloxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol hydrogen L-tartrate (126 mg: yield 56%) as colorless powder.
NMR spectrum (~ value; CD30D): 1.42(1,5H,s), 1.43(1.5H,s), 1.67(1.5H,s), 1.74(3H,s), 1.60 to 2.60(71I,m), 2.81(1.5H,s), 3.00(1.5H,s), 3.11(1H,t,6Hz), 3.33(15H,s), 3.35(1.5H,s), 3.45(2H,m), 3.90 to 4.15(1H,m), 4.41(2H,s), 4.43(1H,s), 4.44(1H,s), - 4.66(0.5H,d,13Hz), 4.70(1H,s), 4.94(0.5H,d,13Hz), 5.22(lH,m), 5.45(lH,m).
[o~]24 28 4 (c 0.20, CHC~3).
Elemental Analysis for C3lH44NOl2SC1.1.5H2O
Calcd. C:51.91%, H:6.61%, N:1.95%, Found C:51.91%, H:6.70%, N:1.99%.
Example 77 1-Benzylmethylsulfoniomethyl-4-chloroacetyl-carbamoyloxy-2-(1,2-ep~xy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol hydrogen succinate Likewise in Example 75, from l~benzylmethyl-sulfoniomethyl-4-Chloroacetylcarbamoyloxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol bromide (200 mg) was obtained 1-benzylmethylsulfoniomethyl-4-chloroacetylcarbamoyloxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol hydrogen succinate (102 mg: yield 48%) as colorless po~der.
NMR spectrum (~ value: CD30D): 1.42(1.5H,s), 1.43(1.5H,s), 1.68(1.5H,s), 1.74(3H,s), 2.51t4H,s), 2 ~
1.60 to 2.60(7H,m), 2.80(1.5H,s), 3.00(1.5H,s), 3.ll(1H,t,6Hz), 3.32(1.5H,s), 3.34(1.5H,s), 3.45(2H,m), 3.90 to 4.15(1H,m), 4.42(2H,s), 4.42(1H,s), 4.43(1H,s), ~.66(0.5H,d,13Hz), 4.70(1H,s), 4.94(0.5H,d,13Hz), 5.22(lH,m), 5.45(lH,m).
~]D -29.7 (c 0.22, C~ICQ3).
Elemental Analysls for C3lH44NOloscl~H2o :
Calcd. C:55.06%, H:6.86~, N:2.07%, Found C:55.28%, H:6.65%, N:1.84%.
Example 78 l-Benzylmethylsulfoniomethyl-4-chloroacetylcarbamoyloxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol hydrogen oxalate Likewise in Example 75, ~rom l-benzylmethyl-sulfoniomethyl-4-chloroacetylcarbamoyloxy-2-(1,2-epoxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl) 3-methox-ycyclohexanol bromide (200 mg) was obtained 1-benzyl-methylsulfoniomethyl-4-chloroacetylcarbamoyloxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol hydrogen oxalate (151 mg: yield 74%) as colorless powder.
NMR spectrum (~ value; CD30D): 1.42(1.5H,s), 1.43(1.5H,s), 1.68(1.5H,s), 1.74(3H,s), 1.60 to 2.60(7H,m), 2.80(1.5H,s), 3.00(1.5H,s), 3.11(1H,t,6Hz), 3.32(1.5H,s), 3.34(1.5H,s), 3.45(2H,m), 3.90 to 4.15(1H,m), 4.42(2H,s), 4.42(1H,s), 4.43(1H,s), 4.66(0.5H,d,13Hz), 4.70(1H,s), 4.94(0.5H,d,13H2), 5.22(1H,m), 5.45(1H,m).
[~]D4-28.4O (c 0.21, CHCQ3).
Elemental Analysis for C2sH4oNoloscl~H2o Calcd. C:53.74%, H:6.53%, N:2.16%, Found C:54.49%, H:6.41%, N:2.10%.
Example 79 2-(1,2-Epoxy-1,5-dimethyl-4-hexenyl)-1-(2-~ 3~3t~
. 99 _ hydroxymethylbenzyl~thiomethyl-3-methoxy-1,4-cyclohexanedlol To an about 14~ methanol solution (6 ml) of sodium methoxide were added, under ice-cooling, 2-mercaptomethylbenzylalcohol (655 m~ and fumagillol (1.00 g). The mixture was stirred ~or one hour at room temperature, to which was added water to suspend the reaction. The product was extracted with ethyl acetate, The extrac~ solution was washed with a saturated aqueous solution o~ sodium chloride, then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (carrier 30 g, developing solvent :
lS ethyl acetate - hexane = 2:1) to give 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(2-hydroxymethylbenzyl)-thiomethyl-3-methoxy-1,4-cyclohexanediol (1.43 g :
yield 92%) as a colorless oily substance.
NMR spectrum (~ value; CDC~3): 1.39(3H,s), 1.66(3H,s), 1.75(3H,s), 1.55 to 1.85(4H,m), 2.00 to 2.55(3H,m), 2.84(1H,d,13Hz), 2.93(1H,d,13Hz), 2.94(1H,t,6Hz), 3.28(1H,m), 3.32(3H,s), 3.86(1H,d,13Hz), 3.96(1H,d,13Hz), 4.20(1H,m), 4.77(2H,br d,6Hz), 5.19(1H,m), 7.20 to 7.50(4H,m).
Example 80 2-(1,2-Epoxy-1,5-dimethyl-4-hexenyl)-1-(2-methanesulfonyloxymethylbenzyl)thiomethyl-3-meth 1,4-cyclohexanediol In dichloromethane (O.S ml) were dissolved 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(2-hydroxymethyl-benzyl)thiomethyl-3-methoxy-1,4-cyclohexanediol (100 mg) ~nd triethylamine (64 ~1). To the solution was added dropwise, under ice-cooling, methanesulfonylchloride (20 ~1). The mixture was stirred for 15 minutes, to which was added water to $ ~
suspend the reaction. The product was extracted with ethyl acetate. The extract solution was washed with a saturated aqueous sol~ltion of sodium chloride, which was then dried over anhydrous magnesium sulfate. The solvent was distilled of~ under reduced pressure. The residue was purified by means o~ a sili~a gel column chromatography (carrier 10 g, developing solvent: ethyl acetate - hexane = 2:1) to give 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(2-methanesulfonyl-oxymethylbenzyl)thiomethyl-3-methoxy-1,4-cyclohexanediol (98 mg: yield 83%) as a colorless oily product.
NMR spectrum (S value; CDC~3): 1.40(3H,s), 1.67(3H,s), 1.74(3H,s), 1.45 to 1.90(4H,m), 2.00 to 2.55(3H,m), 2.89(2H,s), 2.93tlH,t,6Hz), 2.95(3H,s), 3.27(1H,m), 3.33(3H,s), 3.85(1H,d,13Hz), 3.96~lH,d,13Hz), 4.21(lH,m), 5.20(lH,m), 5.42(1H,d,12Hz), 5.49(1H,d,12Hz), 7.25 to 7.50(4H,m).
Example 81 2-(1,2-Epoxy-1,5-dimethyl-4-hexenyl)-(1,3-dihydrobenzo[c~thiophen-2-ylio)methyl-3-methoxy-1,4-cyclohexanediol mesylate In dichloromethane (1 ml) was dissolved 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-t2-methanesulfonyl-oxymethylbenæyl)thiomethyl-3-methoxy-1,4-cyclohexanediol (900 mg). The solution was stirred for 24 hours at 30C. The solvent was distilled off under reduced pressure. The residue was pulverized with ether to give 2-(1 r 2-epoxy-1,5-dimethyl-4-hexenyl)-1-(1,3-dihydrobenzo[c]thiophen-2-ylio)methyl-3-methoxy-1,4-cyclohexanediol mesylate (889 mg: yield 98%) as colorless powder.
NMR spectrum (~ value; CD30D): 1.28(3H,s), 1.63(3H,s), 1.72(3H,s), 1.50 to 2.45(7H,m), 2.70(3H,s), 3.02(1H,m), 3.34(3H,s), 3.40(1H,m), 3.45(1H,d,13Hz), 3.89(1H,d,13~z), 4.78(1H,d,14Hz), 4.95 to 5.25(4H,m), 5.49(1H,m), 7.40 to 7.60(4H,m).
Example 82 4-(N-Chloraacetylcarbamoyloxy)-2-(1,2-epoxy-1,5-d.imethyl-4-hexenyl)-1-(1,3-dihyd.robenzo~c]thiophen-2-ylio)methyl-3-methoxycyclohexanol chloride In dichloromethane (2 ml) was dissolved 2-(1,2-epoxy-1,5 dimethyl-4-hexenyl)-1-(1,3-10 dihydrobenzo[c]thlophen-2-ylio)methyl-3-methoxy-1,4-cyclohexanediol mesylate (500 mg). To the solution was added dropwise, under ice-cooling, chloroacetylisocyanate (0.25 ml). The mixture was stirred for 15 minutes, to which was added water to 15 suspend the reaction. The product was extracted with ethyl acetate. The extract solution was dried over anhydrous magnesium sulfate, then the solvent was distilled off unde.r reduced pressure. The residue was purified by means of a silica gel column chromatography 20 (carrier 40 g, developing solvent : chloroform-methanol = 20:1) to give 4-(N-chloroacetylcarbamoyloxy)-2-(1,2-epox~-1,5-dimethyl-~-hexenyl)-1-(1 t 3-dihydrobenzo[c]thiophen-2-ylio)methyl-3-m-ethoxycyclohexanol chloride (88 mg: yield 13%) as 25 colorless powder.
NMR spectrum (~ value; CD30D): 1.28(3H,s), 1.63(3H,s), 1.71(3H/s), 1.50 to 2.45(7H,m)~ 3.02(1H,m), 3.33(3H,s), 3.51(1H,m), 3.52(1H,d,13Hz), 3.93(1H,d,13Hz), 4.23(2H,s), 4.86(1H,d,16Hz), 5.00 to 30 5.25(4H,m), 5.49(1H,m), 7.40 ~o 7.60(4H,m).
[~]D22-36.8 (c 0.22,CHC~3).
Elemental AnalysiS for C27H37NO6SC12-H2O:
Calcd. C:54.73%, H:6.63%, N:2.36%, Found C:54.65%, H:6.64~, N:2.40%.
Example 83 f~
2-(1,2-Epo~y-1,5-dimethyl-4-hexenyl)-1-(4-hydroxybutylyl)thiomethyl-3-methoxy-1,4-cyclohexanediol Likewise in Example 79, 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(2-hydroxybutylyl)thiomethyl-3-methoxy-1,4-cyclohexanediol was obtained a5 a colorless oily product (yield 79~).
NMR spectrum (~ value; CDC~3~: 1.46(3H,s), 1.67(3H,s), 1.75(3H,s), 1.45 to 1.90(8H,m), 2.00 to 2.70(5H,m), 2.89(2H,s), 2.97(1H,t,6Hz), 3.28(1H,m), 3.35(3H,s), 3.66(2H,m), 4.21(1H,m), 5.20(1H,m).
Example 84 2-(1,2-Epoxy-1,5-dimethyl-4-hexenyl)-1-(4-methanesulfonyloxybutylyl)thiomethyl-3-methoxy-1,4-cyclohexanediol Likewise in Example 80, 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(4-methanesulfonyloxybutylyl)thiomethyl-3-methoxy-1,4-cyclohexanediol as a colorless oily product (yield 92%) NMR spectrum (~ value; CDC~3): 1.46(3H,s), 1.67(3H,s), 1.74(3H,s), 1.45 to 1.95(4H,m), 2.00 to 2.55(3H,m), 2.64(2H,t,7Hz), 2.90(2H,s), 2.99(1H,t,6Hz), 3.02(3H,s), 3.27(1H,m), 3.34(3H,s), 4.23(1H,m), 4.25(2H,t,6Hz), 5.19(1H,m).
Example 85 2-(1,2-Epoxy-1,5-dimethyl-4-hexenyl)-3-methox~-1-~1-tetrahydrothienylio)methyl-1,4-cyclohexanediol mesylate Likewise in Example 81, 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-(1-tetrahydrothienylio)methyl-1,4-cyclohexanediol mesylate was obtained as colorless powder (yield 100%).
~MR spectrum (~ value; CD30D): 1.43(3H,s), 1.69(3H,s), 1.75(3H,s), 1.55 to 2.55(11H,m), 2.70(3H,s), 3.13(1H,m), 3.35(3H,s), 3.40 to 4.00(7H,m), 4.27(lH,m), 5.24(lH,m).
~ ~ 2 '~
Example 86 4-(N-Chloroacetylcarbamoyloxy)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-(1-tetrahydrothienylio)methylcyclohexanol chloride Likewise in Example 82, ~-(N-chloroacetyl-carbamoylo.~y)-2-(1,2-epoxy-1,5-dimethyl-~-he~enyl)-3-methoxy-l-(1-~etrahydrothienylio)methylcycl~hexanol chloride was obtainec~ as colorless powder (yield 95%).
NMR spectrum (~ value; CD30D)~ 3(3H,s), 1.68(3H,s), 1.75(3H,s), 1.60 to 2.55(11H,m), 3.12(1H,t,SHz), 3.34(3H,s), 3.~0 to 4.0S(7H,m), 4.44(2H,s), 5.23(1H,m), 5.47(1H,m).
[~]22-46.8 (c 0.20, CHC~3).
Elemental Analysis for C23H37NO8SC12.1.5H2O
Calcd. C:49.91~, H:7.28%, N:2.58%, Found C:50.07%, H:7.29%, N:2.85%.
Example 87 1-(2-Chloromethylbenzyl)thiomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol In dimethylformamide (0.5 ml) ware dissolved 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(2-hydroxymethylbenzyl)thiomethyl-3-methoxy-1,4-cyclohexanediol (100 mg) and trie~hylamine (64 ~ o the solution was added, under ice-cooling, lithium chloride (21 mg). To the mixture was added dropwise~
methanesulfonyl chloride (20 ~1), which was stirred for 3 hours, then the reaction was suspended by the addition of water. The product was extracted with ether, and the extract solution was washed with 2 saturated aqueous solution of sodium chloride, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (carrier 10 g, developing solvent ~ 3 : ethyl acetate - hexane =1:2) to give 1-(2-chloromethylbenzyl)thiomethyl-2-(1,2-epoxy-1,5-dimet-hyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol (70 mg:
yield 67~) as a colorless oily product.
NMR spe~trum (~ value; CDC~3): 1.~0(3H,s), 1.66(3H,s), 1.74(3~1,s), 1 45 to 1.90(4H,m), 2.00 to 2.55(3H,m), 2.89(2H,s), 2.96(lH,t,6~Iz), 3.27(lH,m), 3.33(3H,s), 3.90(1H,d,13Hz), 3.99(1H,d,13Hz), 4.21(1H,m), 4.76(1H,d,12Hz), 4.83(1H,d,12Hz), 5.20(lH,m), 7.20 to 7.40(4H,m).
Example 88 4-(N-Chloroacetylcarbamoyloxy)-1-(2-chlorometh~lbenzyl)thiomethyl-2-(l~2-epoxy-lr5 dimethyl-4-hexenyl)-3-methoxycyclohexanol In dichloromethane (1.5 ml) was dissolved 1-(2-chloromethylbenzyl)thiomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol (300 mg). To the solution was added dropwise, under ice-cooling, chloroacetylisocyanate (84 ~1). The mixture was stirred for 15 minutes, to which was added water to suspend the reaction. The product was extracted with ethyl acetate. The extract solution was washed with a saturated aqueous solution of sodium chloride, followed by drying over anhydrous magnesi~m sul~ate. The solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (carrier 30 g, developing solvent :
methyl acetate - hexane = 1:2) to give 4-(N-chloroacetylcarbamoyloxy)-1-(2-chloromethylbenzyl)-thiomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol (302 mg: yield 79%) as colorless powder.
NMR spectrum (~ value; CDC~3): 1.41(3H,s), 1.66(3H,s), 1.73(3H,s), 1.50 to 1.90(4H,m), 2.00 to 2.55(3H,m), 2.87(1H,d,13Hz), 2.92(1H,t,6H~), 2.98(1H,d,13Hz), 3.29(1H,m), 3.30(3H,s), 3.91(1H,d,13Hz), 4.01(1H,d,13Hz), 4.50(2H,s), 4.76(lH,d,12Hz), 4.84(1H,d,12Hz), 5.17(1H,m), 5.43(lH,m), 7.20 to 7.40(4~I,m).
~a]22-33.4 (c 0.20, CHC~3).
El~mental Analysis for C27H37NO6SC12 Calcd. C:56.44%, H:6.49%, N:2.44%, Found C:56.23%, H:6.55~, N:2.19%
Example 89 4-Carbamoyloxy-1-(2-chloromethylbenzyl)thiomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol In methanol (2 ml) was dissolved 4-(N~
chloroacetylcarbamoyloxy)-1-(2-chloromethylbenzyl)-thiomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol (193 mg). To the solution was added a standard buffer solution (2 ml) of pH 10, and the mixture was stirred for 5 hours. To the reaction mixture was added water, then the product was extracted with ethyl acetate. The extract solution was washed with a saturated aqueous solution of sodium chloride, which wa9 then dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure,then the residue was purified by means of a silica gel column chromatography (carrier 30 g, developing solvent: methyl acetate - hexane = 1:2) to give 4-(carbamoyloxy-1-(2-chloromethylbenzyl)thiomethyl-2-(1,2-epoxy-l,S-dimethyl-4-hexenyl)-3-methoxycyclohexanol (139 mg :
yield 83%) as a colorless oily product.
NMR spectrum (~ value; CDC~3): 1.42(3Hjs), 1.66(3H,s), 1.74(3H,s), 1.45 to 1.90(4H,m), 2.00 to 2.55(3H,m), 2.87(1H,d,13Hz), 2.94(1H,t,6Hz), 2.98(1H,d,13Hz), 3.27(1H,m), 3.32(3H,s), 3.91(1H,d,13Hz), 4.01(1H,d,13Hz), 4.66(2H,br s), ~ 106 -4.76(1H,d,12Hz), 4.84(1H,d,12Hz), 5.18(1H,m), 5.31(lH,m), 7.20 to 7.40(~H,m).
[~ 22 -24.7 (c 0.20, CHCR3).
Example 90 l-Benzylmethylsulfon.iomethyl-~-chloroacetylcarbamoyloxy-2-(1,2-epoxy-1,5-dimethyl--4-hexenyl)-3-methoxycyclohexanol hydrogen I.-malate L.ikewise in Example 75, from 1-benzylmethylsulfoniomethyl-4-chloroacetylcarbamoyloxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol bromide (200 mg) was obtained 1-benzylmethylsulfoniomethyl-4-chloroacetylcarbamoyloxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol hydrogen Il-malate (120 mg: yield 55%) as colorless powder.
NMR spectrum (~ value; CD30D): 1.42(1.5H,s), 1.43(1.5H,s), 1.68(1.5H,s), 1.74(3H,s), 1.60 to 2.60(7H,m), 2.52(1H,dd,7Hz,16Hz), 2.79(1H,dd,6Hz,16Hz), 2.80(1.5H,s), 3.00(1.5H,s), 3.11(1H,t,6Hz), 3.33(1.5H,s), 3.35(1.5H,s), 3.45(2H,m), 3.90 to 4.15(1H,m), 4.29(1H,dd,6Hz,7Hz), 4.42(1H,s), 4.43(1H,s), 4.66(0.5H,d,13Hz), 4.72(1H,s), 4.94(0.SH,d,13Hz), 5.22(lH,m), 5.45(lH,m).
[~]24-11.3 (c 0.21, CHC~3).
Elemental Analysis for C31H44NOl1SC1.1.5H2O:
Calcd. C:53.10%, H:6.76%, N:2.00%
Found C:53.21~, H:6.55%, N:2.30%
Example 91 4-(2-Benzothiazolylthio)thioacetylcarbamoyl-l-chloromethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol O-Chloroacetylcarbamoyl fumagillol (200 mg) was dissolved in dimethylformamide (2 ml). To the solution was added 2-mercaptobenzothiazol.sodium salt (141 mg), and the mixture was stirred for 30 minutes. To the reaction mixture was dilu~ed with i.sopropylether (50 ml), which was washed with a saturated aqueous solution o~ sodium hydrogencarbonate and a saturated a~ueous solution of sodium chloride, followed by drying over anhydrous ma~nesium sulfate. The solvent was distilled ofE under reduced pressure. The residue was di.ssolved in metharlol (5 ml), to which was added 1 N HCl (1 ml), and the mixture was stirred for 30 minutes. The raaction mixture was diluted with ethyl acetate (50 ml), which was diluted with a satura~ed aqueous solution of sodi~ chloride, a saturated aqueous solution of sodium hydrogen carbonate and further with a saturated aqueous solution of sodium chloride, followed by drying o~er anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure.
The residue was purified by means of a silica gel column chromatography (carrier 20 g, developing solvent: ethyl acetate - hexane = 1:1) to give 4-(2-benzothiazolylthio)thioacetylcarbamoyl~1-chloromethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)--3-methoxychlorohexanol (185 mg: yield 65%) as a colorless oily product.
NMR spectrum (~ value; CDCQ3): 1.42(3H,s), 1.65(3H,s), 1.74(3H,s), 1.45 to 1.90(4H,m), 2.00 to 2.55(3H,m), 2.94(1H,t,6Hz), 3.30(lH,m), 3.33(3H,s), 3.4g(1H,d,llHz), 3.73(1H,d,llHz) r 4.15(1H,d,lSHz), 4.24(lH,d,15Hz), 5.18(lH,m), 5.50(lH,m), 7.30 to 7.55(2H,m), 7.79(1H,d,8Hz), 7.94(1H,d,7Hz).
Elemental Analysis for C26H33N2O6S2Cl:
Calcd. C:54.87%, H:5.84%, N:4.92%r Found C:54.78%, H:5.75%, M:4.72%.
Example 92 2-(1,2-Epoxy-l,S-dimethyl-4-hexenyl)-1-(2-hydroxyethyl)thiomethyl-3-methoxy-1,4-cyclohexanediol ~ ~t~
Likewise in Example 79, 2-(1,2-epoxy-1,5~dimethyl-4-hexenyl)-1-(2-hydroxyethyl)thiomethyl-3-methoxy-1,4-cyclohexanediol (yield 51~) was obtained as colorless powder.
N~ spectrum (~ value; CDC~3): 1.46t3H,s), 1.67(3H,s), 1.75~3~,s), 1.50 to 1.90(4H,m), 2.00 to 2.55(3~1,m), 2.75 to 3.05(5H,m), 3.29(1H,m), 3.34(3H,s), 3.76(1H,q,6Hz), 4.22(1H,m), 5.20(1H,m).
Example 93 1-(4-Chlorobenzyl)thiomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol Likewise in Example 21, 1-(4-chlorobenzyl)thiomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol was obtained (yield ~6%) as a colorless oily product.
NMR spectrum (~ value, CDCQ3): 1.39(3H,s), 1.66(3H,s), 1.74(3H,s), 1.45 to 1.90(4H,m), 2.00 to 2.55(3H,m), 2.80(2H,s), 3.23(1H,t,6Hz), 3.23(1H,m), 3.33(3H,s), 3.71(1H,d,13Hz), 3.75(1~,d,13Hz), 4.20(1~,m), 5.18(lH,m), 7.26(4H,m).
Example 94 2-(1,2-Epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-4-methylthioacetylcarbamoyloxy-1-methylthiomethylcyclohexanol In dimethylformamide (3 ml) was dissolved 4-O-chloroacetylcarbamoyl-2-(1,2-epoxy-1,5-dimethyl-4-hex-enyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (500 mg). To the solution was added thiomethoxide (15 mg), and the mixture was stirred for one ho~x. The reaction mixture was diluted with ether (S0 ml), which was washed with a saturated aqueous solution of sodium chloride, ~ollowed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (carrier 25 g, developing solvent: ethyl acetate - hexane = 2:1) to give 2-(1,2-epoxy-1,5-dimethyl-~-hexenyl)-3-methoxy-4-methylthioacetylcarbamoyloxy-l-methylthiomethylc~clohexanol (407 mg: ~ield 79~) ascolorless powder.
NMR spectrum (~ value; CDC~): 1.47(3H,s), 1.66(3H,s), 1.73(3H,s), l.~S to 1.95(~H,m), 2.00 to 2.55(3H,m), 2.19(3H,s), 2.21(3H,s), 2.86(1H,d,13H~), 2.90(1~,t,6Hz), 2.98(1H,d,13Hz), 3.32(3H,s), 3.33(1H,m), 3.52(1H,d,lSHz), 3.63(1H,d,15Hz), 5.19(lH,m), 5.45(lH,m).
Example 95 4-Benzylthioacetylcarbamoyloxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethylcyclohexanol In dimethylformamide (2 ml) was suspended 60%
sodium hydride (67 mg), to which was added dropwise ~0 benzylmercaptan (O.lS ml). The mixture was stirred for 15 minutes, to which was then added ~-O-chloroacetylcarbamoyl-2-(1,2-epoxy-1,5-dimethyl-4-hex-enyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (500 mg). The mixture was stirred for further one hour. To the reaction mixture was added water to suspend the reaction, and the product was extracted with ether. The extract solution was washed with a saturated aqueous solution of sodium chloride, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under redused pressure, and the residue was purified by means of a silica gel column chromatography (carrier 25 g, developing solvent: ethyl acetate - hexane = 1:2) to give 4-benzylthioacetylcarbamoyloxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethylcyclohexanol (397 mg: yield 66%) as a colorless oily product.
NMR spectrum (~ value; CDCQ3): 1.47(3H,s), 1.66(3H,s), 1.73(3H,s), 1.50 to 1.90(4H,m), 2.00 to 2.55(3H,m), 2.21(3H,s), 2.86(lH,d,13Hz), 2.94(1H,t,6Hz), 2.98(1~1,d,13Hz), 3.32(3H,s), 3.33(lH,m), 3.44(lH,d,lSHz), 3.52(1H,d,15Hz), 3.~9(2EI,s), 5.19(lEI,m), S.43(1H,m), 7.20 ko 7.45(5I~,m).
E~ample 96 1-Bromomethyl-4-chloroacetylcarbamoyloxy-2-(1,2-epoxy-10 1,5-dime~hyl-4-hexenyl)-3-methoxycyclohexanol Likewise in Example 2, from 1-bromomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol (200 mg) was obtained 1-bromomethyl-4-chloroacetylcarbamoyloxy-2-(1,2-epoxy-1,5-dimethyl-4-15 hexenyl)-3-methoxycyclohexanol (178 mg : yield 63~) as colorless crystals, m.p. 111 to 112C.
NMR spectrum (~ value; CDC~3): 1.47(1H,m), 1.51(3H,s), 1.66(3H,s), 1.74(3H,s), 1.70 to 2.55(7H,m), 2.96(lH,d,6Hz), 3.29(lH,m), 3.32(3H,s), 20 3.45(1H,d,lOHz), 3.75(1H,d,lOHz), 4.51(2H,s), 5.18(lH,m), 5.45(lH,m).
[~]23 97 5 (c 0.20, CHC~3).
Elemental Analysis for Cl9H~9NO6SBrCl:
Calcd. C:47.27%, H.6.05%, N:2.90%
Found C:47.18%, H:6.07%, N:2.84%
Example 97 4-Amino-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(2~
hydroxymethylbenzyl)thiomethyl-3-methoxycyclohexanol To an about 7% methanol solution (2.01 ml) of sodium methoxide were added, under ice-cooling, a methanol solution (0.5 ml) of 2-mercaptomethylbenzylalcohol (165 mg~ and a methanol solution (0.5 ml) of 6-oxo-6-desoxyfumagillol (300 mg).
The mixture was stirred for one hour at room temperature, followed by addition of water to suspend the reaction. The reaction mixture was subjected to extraction with ethyl acetate. The 0xtract solution was washed with a saturated aqueous soluti.on of sodium chloride, -then dr.ied over anhydrous ma~nesium sulfate.
The solvent was distilled o~f under reduced pressure, and the residue was purified by means o~ a silica gel column chromatography (carrier 30 g, developing solvent: ethyl acetate - hexane = 2:1) to give 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(2-hydroxymethylbe-nzyl)thiomethyl-3-methoxy-4-oxocyclohexanol (397 mg:
yield 85%) as a colorless oily product.
NMR spectrum (~ value; CD~3): 1.39(3H,s), 1.66(3H,s), 1.73(1H,m), 1.74(3H,s), 2.00 to 2.55(4H,m), 2.40(1H,t,6Hz), 2.65 to 3.05(3H,m), 2.95(1H,d,6Hz), 3.3g(3H,s), 3.84(1H,d,12Hz), 3.92(2H,d,6Hz), 4.01(1H,m), 4.77(2H,d,6~Iz), 5.18(1H,m), 7.20 to 7.45(4H;m)-2-(1,2-Epoxy-1,5-dimethyl-4-hexenyl)-1-(2-hydroxymethylbenzyl)thiomethyl-3-methoxy-4-oxocyclohexanol (1.07 g) and ammonium acetate (1.86 g) were dissolved in methanol (25 ml). To the solution was added sodium cyanoborohydride (304 mg), and the mixture was stirred for one hour. The solvent was distilled off under reduced pressure, and the.residue was dissolved in ethyl acetate (100 ml). The solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (carrier 40 g, developing solvent: chloroform-methanol-NH40H
-20:1:0.1) to obtain 4-amino-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(2-hydroxymethylbenzyl)thiomethyl-3-methoxycyclohexanol (629 mg; yield 58%) as a colorless oily product.
NM~ spectrum (~ value; CDC~3): 1.35 to l.90(~H,m), 1.39(3Hrs), 1.66(3~,s), 1.74(3H,s), 2.05 to 2.55(3H,m), 2.90(2H,s), 2.96(1H,-t,6Hz), 3.25(1H,m), 3.2B(3H,s), S 3.52(1H,d,13Hæ), 3.99(2H,d,13Hz), 4.74(1H,d,12Hz), 4.81(lEI,d,12Hæ), 5.19(1H,m), 7.20 to 7.45(4H,m).
Example 98 4-(N'-chloroacetylureido)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(2-hydroxymethylbenzyl)thiomethyl-3-methoxycyclohexanol In dichloromethane (20 ml) was dissolved 4-amino-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(2-hydroxy-methylbenzyl)thiomethyl-3-methoxycyclohQxanol (629 mg).
To the solution was added dropwise, under ice-cooling, chloroacetyl isocyanate (0.22 ml). The mixture was stirred for 10 minutes, to which was then added water to suspend the reaction. The reaction product was extracted with ethyl acetate. The extract solution was washed with a saturated aqueous solution of sodium chloride and, then, dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by means o~ a silica gel column chromatography (carrier 30 g, developing solvent: ethyl acetate - hexane = 3:2) to a~ford 4-(N'-chloroacetylureido)-2-(1,2-epoxy-1,5-dimethyl-4-hex-enyl)-l-(2-hydroxymethylbenzyl)thiomethyl-3-methoxycyclohexanol (514 mg: yield 64%) as a colorless powdery product.
NMR spectrum (~ value; CDC~3): 1.40(3H,s), 1.45 to 2.55(6H,m), 1.65(3H,s), 1.73(3H,m), 2.65(1H,t,6Hz), 2.83(1H,d,13Hz), 2.96(1H,t,6Hz), 2.97(1H,d,13Hz), 3.30(3H,s), 3.35(1H,dd,4Hz,llHz), 3.86(1H,d,13Hz), 3.94(1H,d,13Hz), 4.15(2H,s), 4.47(1H,m), 4.75(1H,dd,6Hz,13Hz), 4.81(1H,dd,6Hz,13Hz), 5.17(1H,m), 7.20 to 7.45(4H,m), 8.25(2H,m).
Example 99 4-(N'-chloroacetylureido)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(2-methanesul~onyloxyJnethylbenzyl)t~liomethyl-3-me-thoxycyclohex~nol In dichloromethane (3 ml) were dissolved 4-(N'-chloroacetylureido)-2-(1,2 epoxy-l,S-dimethyl-4-hex-enyl)-1-(2-hydroxymethylbenz~l)thiomethyl-3-methoxycyclohexanol t514 mg) and triethylamine (0.33 ml). To the solution was added dropwise at -20C
methanesulfonyl chloride (96 ~Q). The mixture was stirred for 10 minutes, to which was added water to suspend the reaction. The reaction product was extracted with ethyl acetate. The extract solution was washed with a saturated aqueous solution o~ sodium chloride and, then, dried over anhydrous magnesium sulfate. The solvent was distilled o~ under reduced pressure to leave 4-(N'-chloroacetylureido)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(2-methanesulfonyloxymethylbenzyl)thiomethyl-3-me-thoxycyclohexanol (550 mg; yield 98%) as a colorless powdery product.
NMR spectrum (~ value; CDC~3): 1.40(3H,s), 1.65(3H,s), 1.73(3H,s), 1.45 to 1.95(4H,m), 2.00 to 2.55(3H,m), 2.81(1H,d,14Hz), 2.94(3H,s), 2.97(1H,d,14Hz), 2.98(1H,t,6Hz), 3.30(3H,s), 3.35(1H,m), 3.86(1H,d,13Hz), 3.96(1H,d,6Hz), 4.16(3H,br s), 4.48(1H,m), 5.26(1H,m), 5.46(2H,s), 7.15 to 7.55(4H,m), 8.42(1~,m).
Example 100 4-(N'-chloroacetylureido)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-l-(1,3-dihydrobenzo[c]thiophen-2-ylio)methyl-3-methoxycyclohexanol chloride In dichloromethane (2 ml) was dissolved 4-(N'-chloroacetylureido)-2-~1,2-epoxy-1,5-dimethyl-4-hex-enyl)-1-(2-methanesulfonyloxymethylbenzyl)thiomethyl-3-methoxycyclohexanol (450 mg). The solution was sti.rred Eor 24 hou~s ~t 30C. The solvent was distilled of under reduced pressure. To the residue was added water, to which was added sodium chloride to perform saltin~ out. The product was extracted with ethyl acetate. The extract solution was dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. To the residue was added ether to cause pulverization to give 4-(N'-chloroacetylureido)-2-(l~2-epoxy-l~5-dimethyl-4~hex-enyl)-1-(1,3-dihydrobenzo[c]thiophen-2-ylio)methyl-3-methoxycyclohexanol chloride (293 mg: yield 71%) as a colorless powdery product.
NMR spectrum (~ value; CD30~): 1.31(3H,s), 1.64(3H,s), 1.72(3H,s), 1.55 to 2~45(7H,m), 3.07(1H,t,7Hz), 3.31(3H,s), 3.52(1H,d,13Hz), 3.56(lH,dd,4Hz,lOHz), 3.91(lH,d,13Hz), 4.19(2H,s), 4.42(lH,m), 4.81(lH,d,16Hz), 4.95 to 5.25(4H,m), 7.40 to 7.60 (4H,m).
[~]22_ 31.8 (c 0.21, CHCQ3).
Elemental Analysis for C27H38N2O5SC12.0-5H2O :
Calcd.: C:55.66%, H:6.75%, N:4.81~, Cl:12.17%, S:5.50%
Found : C:55.50%, H:6.73%, N:4.63%, C1:11.65%, S:5.84%
Example 101 2-(1,2-Epoxy-1,5-dimethyl-4-hexenyl)-1-(3,4,5,6-tetrafluoro-2-hydroxymethylbenzyl)thiomethyl-3-methoxy-1,4-cyclohexanediol Likewise in Example 79, from fumagillol (249 mg) was obtained 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(3,4,5,6-tetrafluoro-2-hydroxymethylbenzyl)thiomethyl-3-methoxy-1,4-cyclohexanediol (350 mg: yield 77%) as a colorless oily product.
~R spectrum (~ value; CDC~3): 1.40(3H,s), r~
1.66(3H,s), 1.75(3H,s), 1.75(3H,s), 1.55 to 1.85(4H,m), 2.00 to 2.50(3H,m), 2.89(1H,d,13Hz), 2.92(1H,t,7Hz), 2.97(1H,d,13Hz), 3.20(1H,m), 3.31(3H,s), 3.~8(1~I,dd,2Hz,13Hz), 4.03(1H,dd,lHz,13Hz), 4.19(1H,m), 4.77(2H,m), 5.18(lH,m).
Example 102 2-(1,2-Epoxy-l,S-dimethyl-4-hexenyl)-1-(3,4,5,6-tetrafluoro-2-methanesulfonyloxymethylbenzyl)thiomethyl-3-methoxy-1,4-cyclohexanediol Likewise in Example 80, from 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(3,4,5,6-tetrafluoro-2-hydroxymethylbenzyl)thiomethyl-3-methoxy-1,4-cyclohe-xanediol (300 mg) was obtained 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(3,4,5,6-tetrafluoro-2-methanesulonyloxymethylbenzyl)thiomethyl-3-meth ,4-cyclohexanediol (330 mg: yield 95%) as a colorless oily product.
NMR spectrum (~ value; CDCQ3): 1.41(3H,s), l.S6(3H,s), 1.74(3H,s), 1.55 to 1.85(4H,m), 2.00 to 2.50(3H,m), 2.90(1H,d,13Hz), 2.97(1H,t,7Hz), 3.02(1H,d,13Hz), 3.08(3H,s), 3.25(1H,m), 3.94(1H,dd,2Hz,13Hz), 4.02(1H,dd,2Hz,13Hz), 4.21(1H,m), 5.19(1H,m), 5.46(1H,br s).
Example 103 2-(1,2 Epoxy-1,5-dimethyl-4-hexenyl)-1-(6-hydroxymethyl-3-cyclohexenylmethyl)thiomethyl-3-methoxy-1,4-cyclohexanediol Likewise in Example 79, from fumagillol (700 mg) was obtained 2-(1,2-epoxy-l,S-dimethyl-4-hexenyl)-1-(6-hydroxymethyl-3-cyclohexenylmethyl)thiomethyl-3-methoxy-1,4-cyclohexanediol (988 mg: yield 90%) as a colorless oily product.
NMR spectrum (~ value; CDCQ3): 1.46(3H,s), 2 ~
1.67(3H,s), 1.75(3H,s), 1.55 to 2.80(13H,m), 2.96(lH,d,13Hz), 2.98(1H,t,6Hz), 3.30(lH,m), 3.24(3H,s), 3.45 to 3.75(~H,m), 4.22(lH,m), 5.20(lH,m), 5.63(2H,hr s).
Example lO~
4-(N-chloraacetylcarbamoyloxy)-2-(1,2 epoxy-1,5-dimethyl-4-hexenyl)-1~(1,3,3a,4,7,7a-hexahydrobenzo[c]thiophen-2-ylio)methyl-3-methoxycyclohexanol chloride In dichloromethane (3 ml) were dissolved 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-l-(6-hydroxymethyl-3-cyclohexenylmethyl)thiomethyl-3-methoxy-1,4-cyclohexanediol (500 mg) and triethylamine (0.32 ml).
To the solution was added dropwise at -20C
methanesulfonyl chloride (92 ~). The mixture was warmed to room temperature, which was stirred for one hour. The mixture was then cooled on an ice-bath, to which was added dropwise chloroacetyl isocyanate (0.29 ml). The mixture was stirred for lO minutes, to which was then added water to suspend the reaction. To the reaction mixture was added sodium chloride to perform salting-out, followed by extraction with ethyl acetate.
The extract solution was dried over anhydrous magnesium sulfate. The solvent was then distilled o~f under reduced pressure. The residue was purified~by means of a silica gel column chromatography (carrier 20 g, developing solvent: chloroform-methanol = 15:1) to afford 4-(N-chloroacetylcarbamoyloxy)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(1,3,3a,4,7,7a-hexahydrobenzo[c]thiophen-2-ylio)methyl~3-methoxycyclohexanol chloride ~214 mg: yield 27%) as a colorless powdery product.
NMR spectrum (~ value; CD30D)~ 5(3H,s), 1.68(3H,s), 1.75(3H,s), 1.70 to 2.30(8H,m), 2.35 to 2.55(3H,m), 2.85 to 3.05(2H,m), 3.12(1H,t,6Hz), ~ ~ rJ ~
3.34(3H,s), 3.40 to 3.75(5H,m), 3.84(1H,dd,6Hz,13Hz), 4.13~1H,d,13Hz), 4.43(2H,s), 5.24(1H,m), 5.47(1H,m), 5.70(2H,br s).
Example 105 4-amino-2-(1,2 epoxy-1,5-dimekhyl-4-hexenyl)-1-(6-hydroxymethyl-3-cyclohexenylmethyl)thiomethyl-3-methoxycyclohexanol Likewise in Example 97, from 6-oxo-6-desoxyfumagillol, by way of 2~(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(6-hydroxymethyl-3-cyclohexenylmethyl)thiomethyl-3-methoxy-4-oxocyclohexanol, was obtained 4-amino-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(6-hydroxymethyl-3-cyclohexenylmethyl)thiomethyl-3-methoxycyclohexanol as a colorless oily product.
2-(1,2-epoxy-1,5-dimethyl-4-hexenyl) 1-(6-hydroxymethyl-3-cyclohexenylmethyl)thiomethyl-3-methoxy-4-oxocyclohexanol:
NMR spectrum (~ value; CDCl3): 1.46(3H,s), 1.67(3H,s), 1.74(3H,s), 1.65-2.85(13H,m), 2.85-3.10(4H,s), 3.41(3H,s), 3.45~3.75(2H,m), 3.87(1H,d,12Hz), 3.99(1H,dd,2Hz,8Hz), 5.19(1H,m), 5.63(2H,d,2Hz).
4-amino-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(6-hydroxymethyl-3-cyclohexenylmethyl)thiomethyl-3-methoxycyclohexanol:
NMR spectrum (~ value; CDCl3): 1.45(1.5H,s), 1.46(1.5H,s), 1.66(3H,s), 1.74(3H,s), 1.50-3.05(18H,m), 3.25(lH,m), 3.29(3H,s), 3.45-3.75(3H~m), 5.19(1H!m), 5.62(2H,br s).
Example 106 4-(N'-chloroacetylureido)-2-(1,2-epoxy-1,5-dimethyl-4 hexenyl)-1-(6-hydroxymekhyl-3-cyclohexenylmethyl~hiomethyl-3-methoxycyclohexanol Likewise in Example 98, from 4-amino-2-(1,2-epoxy-r3 ~ 118 ~
1,5-dimethyl-4-hexenyl)-1-(6-hydroxymethyl-3-cyclohexenylmethyl)thiomethyl-3-methoxycyclohexanol (870 mg) was obtained 4-(N'-chloroacet~lureido)-2-(1,2-epoxy-1,5-dimethyl-4-he~enyl)-1-(6-hydroxymethyl-3-cyclohexenylmethyl)thiomethyl-3-methoxycyclohexanol (588 mg: yield 53~) as a colorless oily product.
NMR spectrum (~ value; CDCl~): 1.46(1.5H,s), 1.48(1.5H,s), 1.66(3H,s), 1.7~(3H,s), 1.50-3.10(18H,m), 3.31(1.5H,s), 3.32(1.5H,s), 3.25-3.90(4H,m), 4.13(1H,s), 4.14(1~1,s), 4.50(1H,m), 5.17(1H,m), 5.62(2H,br s), 8.43(lH,m), 8.59(lH,m).
Example 107 4-(N'-chloroacetylureido)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(1,3,3a,4,7,7a-hexahydrobenzo~c]thiophen-2-ylio)methyl-3-methoxycyclohexanol chloride In dichloromethane (5 ml) were dissolved ~-(N'-chloroacetylureido)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(6-hydroxymethyl-3-cyclohexenylmethyl)thiomethyl-3-methoxycyclohexanol (500 mg) and triethylamine (0.25 ml). To the solution was added dropwise at -20C methanesulfonyl chloride (69 ~1). The mixture was warmed to room temperature, which was stirred for one hour. The solvent was distilled off under reduced pressure and the residue was dissolved in water. Insolubles were removed off by decantation and to the obtained supernatant liquid was added sodium chloride, followed by salting out. The product was extracted with ethyl acetate. The extr~ct solution was dried over anhydrous magnesium sulfate then the solvent was distilled o~f under reduced pressure. The residue was purified by means of a silica gel column chromatography (carrier 20 g, developing solvent : chloroform - methanol = 15:1) to give 4-(N'-chloroacetylureido)-2-(1,2-epoxy-l,S-dimethyl-4-hexenyl)-1-(1,3,3a,4,7,7a-hexahydrobenzo[c]thiophen-2-ylio)methyl-3-methoxycyclohexanol chloride ~290 mg: yield 56%) as colorless powder.
NMR spectrum (~ value; CD30D): 1.47(3H,s), 1.68~3H,s), 1.75(3H,s), 1.55-2.30(8H,m), 2.35-2.55(3H,m), 2.85-3.05(2H,m), 3.15(1H,t,6Hz), 3.33(3H,s), 3.50-3~65(5H,m), 3.70(1H,d,13Hz), 3.82(1H,dd,6Hz,13Hz), 4.13(1H,d,13Hz), 4.19(2H,s), 4.43(lH,m), 5.23(lH,m), 5.70(2H,br s).
Elemental Analysis for C27H42N2O5SC12-075H2O
Calcd. C:54.86%, H:7.42%, N:4.74%
Found C:54.95%, H:7.76%, N:5.00%
This reaction is conducted usually in the presence of a base. As the base, use is made of those mentioned in the description of the alkylation, and the amount to be added ranges usually from about 1 mol. to 10 times as much mol. relative to 1 mol. of fumagillol.
This reaction is conducted usually in an organic solvent which does not exert undesirable influence on the reaction. As the organic solvent which does not - exert undesirable influence on the reaction, use is made of those mentioned in the description of -the~
alkylation.
While the reaction temperature varies with the ~
amounts, kinds, etc. of chloroformic acid ester, bases and solvents, it ranges from -20C to the reflux temperature of the reaction medium, preferably from 0C
to 50C. The reaction time ranges from about 10 minutes to about 5 days.
And, the compound (III) wherein G i mono- and di-2 ~
~s substituted carbamoyl can be produced also by allowing the compound (III) wherein G is phenoxycarbonyl to react with ammonia, primary ~mines (e.g. methylamine, ethylamine, isopropylami.ne, etc.), or secondary amines (e.g. dimethylamine, ethylmethylamine, dimethylami.ne, pyrrolidine, piperidine, N-methylpiperazine, morpholine, etc.).
Ammonia, primary amines and secondary amines are employed usually in an amount of 1 mol. to 5 times as much mol. relative to 1 mol. of the starting compound.
This reaction is conducted usually in an organic solvent which does not exert undesirable influence on the reaction. As the organic solvent which does not exert undesirable influence, use is made of those mentioned in the description of the alkylation.
~ hile the reaction temperature varies with amounts, kinds, etc. of ammonia, primary amines, secondary amines and solvents, it ranges from -20~C to the reflux temperature of the reaction medium, preferably from 0C to 50C. The reaction times ranges from about 20 minutes to about 5 days.
Reaction step 2. Production of the compound (IV) from fumagillol (II) This reaction can be conducted by, for example in the acylation described in the acylation in the reaction step l, using acid halide as the reactive derivative of carboxylic acid and, as the base, triethylamine or pyridine.
Reaction step 3: Production of the compound (V) from fumagillol (II) This reaction can be conducted by allowing hydrogen halide to react with fumagillol.
Examples of the hydrogen halide include hydrogen bromide, hydrogen iodide, etc., and they are used as an aqueous solution of hydrobromic acid, hydroiodic acid, etc. in general. The hydrogen halide is used in an amount of usually about 1 mol. to 10 times as much mol., preferably 1 to 5 times as much mol. relative to 1 mol. of fumagillol.
This reaction is conducted usually in a sol~ent S which does not exert undesirable influence on the reaction. As the solve~t which does not exert undesirable influence on the reaction, use is made of, for example, water, and alcohols, amides, halogenated hydrocarbons, ethers, esters, nitriles, nitro compounds, ketones, aromatic hydrocarbons, aliphatic hydrocarbons, etc. referred to in the reaction step 1.
These can be used singly or as a suitable combination of two or more species of them.
While the reaction temperatures vary with the amounts, kinds, etc. of hydrogen halide and solvents, they are in the ran~e from -80 to 100C, preferably from 0C to room temperatures (room temperatures mean the range from about 20 to about 35C, and the same applies hereinafter unless otherwise specified). The reaction time ranges from about 30 minutes to about 5 days.
And, the reaction with hydrogen iodide may be conducted in accordance with a ~ se known method [Cornforth, J. W., et al., J. Chem. Soc., 1959, 112].
Reaction step 4: Production of the compound (VI) from fumagillol (II) This reaction is conducted by allowing secondary amines or thiols to react with fumagillol.
As the secondary amines or the thiols, use is made of HNRlR2, HSRl wherein Rl and R2 are of the same meaning as defined for them in the general formula (I), or metal salts thereof, and, as the metal salt, use is made of salts with, for instance, aIkali metals (e.g.
lithium, sodium, potassium, etc.), etc.
The secondary amines or the thiols are used in an amount of usually ranging from about 1 mol. to about 10 . .
'J
times as much mol., preferably 1 to 5 times as much mol., xelative to 1 mol. of fumagillol.
This reaction may be conduc-ted in the presence of a bas0. ~s the base, use is made of tertiary amine, alkali met~l h~drogencarbonates, alkali metal carboantes, alkali metal hydrides, etc. mentioned in the reaction step 1, and the amount to be added ranges usually from about 1 mol. to 10 times as much mol.
relative to 1 mol. of fumagillol.
This reaction is conducted in the absence of solvent or in a solvent which does not exert undesirable influence on the reaction. As the solvent which does not exert undesirable influence, use is made of, for example, solvents referred to in the reaction step 3.
The reaction temperature varies with the amounts, kinds etc. of secondary amines, thiols, bases and solvents, but it ranges from -80C to 100C, preferably from 0C to 50C. The reaction time .ranges from about 30 minutes to about 5 days Reaction step 5: Production of the compound (IV) from the compound (III) This reaction can be conducted by subjecting the compound (III) to the reaction mentioned in the reaction step 3, and, in the reaction mentioned in the reaction step 3, hydrogen chloride or hydrochloric acid may be used as hydrogen halogenide.
Reaction step 6: Production from the compound (IV) ~rom the compound (~) This reaction can be conducted by subjecting the compound (V) to the reaction mentioned in the reaction step 1.
React,ion step 7: Production of the compound (VI) ~rom the compound (V) This reaction can be conducted by subjecting the compound (V) to the reaction mentioned in the reaction ~J~L~
_ 2~ -step 4.
Reaction step 8: Production O:e the compound (VII) from the compound (III) This reaction can be conducted b~ subjecting the compound (III) to the reaction mentioned in the reaction step ~.
Reaction s~ep 9: Production of the compound (VII) from the compound (IV) This reaction can be conducted by subjecting the compound lIV) to the reaction mentioned in the reaction step 4.
Reaction step 10: Production of the compound (X) from the compound (IV) This reaction can be conducted by allowing tertiary amines or sulides to react with the compound (IV).
As the tertiary amines or the sulfides, use is made of NRI~2R3 or SRlR2 wherein RI~R3 are of the same meaning as defined for those in the general formula (I).
The tertiary amine or the sulfides are used in an amount of usually about 1 mol. to 10 times as much mol., preferably 1 to 5 times as much mol., relative to a mol. of the compound (IV).
This reaction can also be conducted in the presence of a base or metal salt. As the base, use is made of the afore-mentioned alkali metal hydrogencarbonates, alkali metal carbonates, etc., and, as the metal salt, use is made of mercury salts (e.g.
mercury iodide, etc.) or silver salts (e.g. silver tetrafluoroborate, silver perchlorate, etc.), etc., and the amount to be added ranges usually from about 1 mol.
to 5 times as much mol. relative to 1 mol. of the compound (IV).
This reaction is conducted in the absence of solvent or in an organic solvent which does not exert 2 ~ v ~
undesirable influence. As the organic solvent which does not exert undesirable influence, use is made of alcohols, ami.des, haloger~ated hydrocarbons, ethers, esters, nitriles, nitro compounds, ketones, aromatic S hydrocarbons, aliphatic saturated hydrocarbons, etc.
mentioned in the reaction step 1, and these solvents may be used singly or as a mixture of two or more of them in a suitable ratio.
The reaction temperature varies with the amount, kinds, etc. of tertiary amines, sulfides, bases, metal salts and solvents, but it ranges from -80C to 100C, preferably from 0C to 50C. The reaction time ranges from about 30 minutes to about 15 days.
Reaction step 11: Production of the compound ~VIII) from the compound (V) This reaction can be conducted by subjecting the compound (V) to the reaction described in the reaction step 10.
Reaction step 12: Production of the compound (VII) from the compound (VI) This reaction can be conducted by subjecting the - compound (VI) to the reaction described in the reaction step 1.
Reaction step 13: Production of the compound (VIII) from the compound (VI) This reaction is conducted by subjecting the compound (VI) to N or S alkylation.
The said alkylation is conducted by allowing an alkylating agent represented by R3J wherein R3 is o~
the same meaning as defined for R3 in the general formula (I), and J stands for a leaving group such as halogen, methanesulfonyloxy group, p-toluenesulfonyloxy group, methoxysulfonyloxy group, trifluromethanesulfonyloxy group, dimethyloxonio-tetrafluoroborate group, diethyloxonio-tetrafluoroborate group, etc. to react 2 ~
with the compound (VI).
The alkylating agent is used usually in a range of from about l mol. to 100 times as much mol. relative to 1 mol. of the compound (VI).
This reaction may be conducted in the presence of a base or a metal salt. As the base, use is made of alkali me~als hydrogencarbonates, alkali metal carbonates, etc. mentioned in the reaction step 1, and, as the metal salt, use is made of mercury salt (e.g.
mercury iodide, etc.), and the amount of such base to be added ranges from about 0.1 mol. to 5 times as much mol. relative to l mol. of the starting alcohol.
This reaction is conducted in the absence of solvent or in an organic solvent which does not exert undesirable influence on the reaction. As the organic solvent which does not exert undesirable influence on the reaction, use is made of amides, halogenated hydrocarbons, ethers, esters, nitriles, nitro compounds, ketones, aromatic hydrocarbons, aliphatic ~0 hydrocarbons, etc., and these can be used singly or as a mixture of two or more of them in a suitable ratio.
The reaction temperature varies with the amounts, kinds, etc. of the alkylating agents, ~ases, metal salts and solvents, but it ranges from -80C to 100C, preferably from 0C to 50C. The reaction time ranges ; from about 20 minutes to about 5 days.
Reaction step 14: Production of the compound (IX) from the compound (VI) This reaction is conducted by subjecting NRlR2 group or SR3 group shown by X in the compound (VI) to oxi.dation.
As the oxidizing agent to be employed for ~he oxidation, use is made of aqueous hydrogen peroxide, periodic acid (e.g. ortho periodic acid, meta periodic acid, etc.) or salts thereof, organic peracids te.g.
performic acLd, peracetic acid, perbenzoic acid 2 ~
methachloroperbenzoic ~cid, etc.) or salts thereof.
This reaction is conducted usually in a solvent which does not exert undesirable influence on the reaction. ~s the solvent which does not exert undesirable in~luence on the reaction, use is made of water, and halogenated hydrocarbons, ethers, aromatic hydrocarbons or aliphatic saturated hydrocarbons mentioned in the reaction step l. These solvents may be used singly or a mixture of two or more of them in a suitable ratio.
The reaction temperature varies with the amounts, kinds etc. of the oxidizing agents and solvents, but it ranges ~rom -80C to 100C, preferably from 0C to 50C. The reac~ion time ranges from about 20 minutes ko 5 days.
Reaction step 15: Production of the compound (X) from the compound (VII) This reaction can be conducted by subjecting the compound (VII) to the reaction described in the -eaction step 13.
Reaction step 16: Production of the compound (X) from the compound (~III) This reaction can be conducted by subjecting the compound (VIII) to the reaction described in the reaction step 1.
Reaction step 17: Production of the compound (XI) from the compound (VIII) This reaction can be conducted by subjecting a compound (VIII) wherein M stands ~or S~RlR2-X~ to the reaction described in the reaction step 14.
Reaction step 18: Production of the compound (XI) from the Compound (IX) This reaction can be conducted by subjecting a compound (IX) wherein L is S(O)Rl to the reaction described in the reaction step 11.
Reaction step 19: Production of the compound (XII) from the compound (IX) This reaction can be conducted by subjecting the compound (IX) to the reaction described in the reaction step 1.
Reaction step 20: Product.ion of the compound (XIII) from the compound (X) This reaction can be conducted by subjecting a compound (X) wherein M is S~RlR2-X~ to the reaction described in the reaction step 14.
Reaction step 21: Production of the compound (XIII) from the compound (XI) This reaction can be conducted by subjecting the compound (XI) to the reaction described in the reaction step 1.
Reaction step 22: Production of the compound (XIII) from the compound (XII) This reaction can be conducted by subjecting a compound (XII) wherein L is S(O)RI to the reaction described in the reaction step ll.
Reaction step 23: Production of the compound (XII) from the compound (VII) This reaction can be conducted by subjecting the compound (VII) to the reaction described in the reaction step 14.
Reaction step 24: Production of the compound (XIV) from fumagillol (II) This reaction is conducted by subjecting fumagillol to oxidation using chromic anhydride in pyridine in accordance with, for example the method of Tarbell e~ al. [Tarbell, D.S.,(J. Am. Chem. Soc.), 77, 5610 (1955)], or to oxidation using pyridinium dichromate in accordance with the method of Goto et al~
(JPA Sho 62-476).
And, in accordance with per se known methods, Jones oxidation [Jones. E.R.H., (J. Chem. Soc.), 1946, 39], Collins oxidation [Collins, J.C., Tetrahedron - .
-` 2 ~ 2 ~
Lett., 1968, 3363], PCC oxidation [Corey, E.J., et al., Tetrahedron Lett., 1975, 2647] or oxidat.ion using the combination of dimethylsulfoxide and an activating agent may be conducted. ~s the activatin~ agent. for dimethylsulfoxide, use can be made of dicyclohexylcarbodiimide [Moffat, J.G., et al. ~. Am.
Chem. Soc., 85, 3027 (1963)], acetic anhydride [Albright, J.D., et al., J. Am. Chem. Soc., 87, 4214 tl965)], phosphorus pentoxide [Onodera et al. J. Am.
Chem. Soc.), 87, 4214 (1965)], sulfur trioxide -pyridine complex [Parikh, J.R., et al., J. Am. Chem.
Soc., 89, 5505 ~1967)], oxalylchloride [Swern, D., et al., J. Org. Chem., 43, 2480 (1978)], etc.
Reaction step 25: Production o~ the compound (XVII) from the compound (XIV) This reaction is conducted by subjecting the compound (XIV), in accordance with a Per se known method [Borch, R.F. et al. ~. Am. Chem. Soc., 93, 2897 (1971)], to reductive amination.
Reaction step 2~: Production of the compound (XV) from fumagillol (II) This reaction can be carried out, in accordance with the scheme 1, by subjecting fumagillol to an~ one of the reactions described in the reaction steps 3, 4, 11, 13, 1~, 17 and 18, or to a suitable combination of them.
Reaction step 27: Production of the compound (XVI) from the compound (2IV) This reaction can be carried out, in a manner similar to the scheme 1, by subjecting the compound (XIV) to any one the reactions described in the reaction steps 3, 4, 11, 13, 14, 17 and 18, or to a suitable combination of them.
Reaction step 28: Production of the compound (XVI) from the compound (XV) This reaction can be carried out by subjecting the 2 ~ d ~
compound (XV) to the reaction described in the reaction step 24. And, transformation o~ the portion ~ may be carried out simultaneously by a suitable combination o the reacti.on described in the reaction step 24 with any o the re~ctions described in the reaction steps 9, 10, 13, 14, 17 and 18.
Reaction step 29: Production of the compound (XIX) from the compollnd (XVI) This reaction can be conducted by subjecting the compound (XVI) to the reaction described in the reaction step 25. And, transformation of the portion A
may be carried out simultaneously by a suitable combination o~ the reaction described in the reaction step 25 with any one of the reactions described in the reaction steps 9, 10, 13, 14, 17 and 18.
Reaction step 30: Production of the compound (XVIII) from the compound (XVII) This reaction can be conducted, in a manner similar to the scheme 1, by subjecting the compound (XVII) to the reaction described in the reaction step 1.
And, in the case of conducting alkylation of the NHR4 group of the compound (XVII), other than the method described in the reaction step 1, a method known as a reductive alkylation [Emoersonr ~.S., Org. React., 4, 174 (1948); or Lane, C.F., Synthesis, 135 (1975)]
may be employed.
Reaction step 31: Production of the compound (XIX) from the compound (XVII) This reaction can be conducted by subjecting the compound (XVII) to the reaction descri~ed in the reaction step 27.
Reaction step 32: Production of the compound (XX) from the compound (XIX) This reaction can be conducted by subjecting the compound (XIX) to the reaction described in the 2~2~3~3 reactlon step 30. And, transformation of the portion A
may be carried out simultaneously by a suitable combinat.ion of the xeaction described in the reaction step 30 with any one of the reactions described in the reaction steps 9, 10, 13, 14, 17 and 18.
Reaction step 33: Production of the compound (XX) from the compound (XVIII) This reaction can be carried out, in a manner similar to the scheme 1, by subjecting the compound (XVIII) to any one of the reactions described in the reaction steps 5, 8, 9, 10, 15, 20, 22 and 23, or to a suitable combination of them.
Reaction step 34: Production of the compound (XXI) from fumagillol This reaction is conducted by subjecting a 6-O-acyl-6-epifumagillol derivative to hydrolysis by a per se known method [~ose, A.K., Tetrahedron Lett., 1973, 1619], the derivative being obtained by sub~ecting fumagillol to the Mitsunobu reaction using diethyl azodicarboxylate and carboxylic acid such as triphenyl phosphine and formi.c acid or benzoic acid [Mitsunobu, O., Synthesis, 1 (19~1)].
Reaction step 35: Production of the compound (XXIII) from the compound (XV) This reaction can be conducted by subjecting the compound (XV) to the reaction described in the reaction step 34. And, trans~ormation of the portion A can be conducted simultaneously by suitable combination of the reaction described in the reaction step 34 with any one of the reactions described in the reactions steps 9, 10, 13, 14, 17 and 18.
Reaction step 36: Synthesis of the compound (XXII) from : the compound (XXI) This reaction can be conducted by subjecting the compound (XXI) to the reaction described in the reaction step 1.
2~3~
Reactlon step 37: Synthesis of the compound (XXV) from the compound (XXIII) This reaction can be conducted by subjecting the compound (XXIII) to a reaction similar eo that described in the reaction step 1. And, transformation of the portion A may be carried out simultaneously by a suitable combination of the reaction described in the reaction step 1 with any one of the reactions described in the reaction steps 9, 10, 13, 14, 17 and 18.
Reaction step 38: Synthesis of the compound (XXIII) from the compound (XXI) This reaction can be conducted by subjecting the compound (XXI) to the reaction described in the reaction step 27.
Reaction step 39: Production o~ the compound (XXIV) from the compound (XXII) This reaction can be conducted by subjecting the compound (XXII) to the reaction described in the : reaction step 33.
Reaction step 40: Production of the compound (XXV) from fumagillol (II) This reaction is conducted by subjecting an imide compound to hydrolysis by means of a ~E se known method [Mitsunobu, O., J. Am. Chem. Soc., 94, 679 (1972)], the imide compound being obtained by subjecting fumagillol to Mitsunobu reaction using diethyl azodicarboxylate, triphenyl phosphine and imide such as phthalimide or succinimide [Mitsunobu, O., Synthesis, l (1981)].
Reaction step 41: Production of the compound (XXIX) from the compound ~XV) This reaction can be conducted by subjecting the compound (XV) to the reaction described in the reaction step 40. And, transformation of the portion A may be simultaneously carried out by sui~able combination of the reaction described in the reaction step 40 with any ~2~
.
one of the reactions described in the reaction steps 9, 10, 13, 14, 17 and 18.
~eaction step 42: Production of the compound (XXIX) ~rom t:he compound (XXV) This reaction can be conducted by subjecting the compound (XXV) to the reaction described in the reaction step 27.
Reaction step 43: Production of the compound ~XXVII) ~ro the compound (XXV) This reaction can be conducted by subjecting the compound (XXV) to N-alkylation by means of a Per se known method ["Comprehensive Organic Chemistry~ Vol. 2, pp. 4 to 11, compiled by Sutherland, I.O., Pergamon Press (1979)].
Reaction step 44: Production of the compound ~XXXI) from the compound (XXIX) This reaction can be conducted by subjecting the compound (XXIX) to the reaction described in the reaction step 43. And, transformation of the portion A
may be carried out by a suitable combination of the reaction described in the reaction step 43 with any one of the reactions described in the reaction steps 9, 10, 13, 14, 17 and 1~.
Reaction step 45: Production of the compound (XXXI) from the compound (XXVII) This reaction can be conducted by subjecting the compound (XXVII) to the reaction described in the reaction step 27.
Reaction step 46: Production of the compound (XXVI) from the compound (XXV) This reaction can be conducted by subjecting the compound (XXV) to the reaction described in the reaction step 30.
Reaction step 47: Production of the compound (XXX) from the compound (XXIX) This reaction can be conducted by subjecting the 2~2~`~3~
compound (XXIX) to the reaction clescribed in the reaction step 30.
Reaction step ~: Production of the compound (XXX) from the compound (XXVI) rrhis reaction can be conducted by subjecting the compound (XXVI) to the reaction described in the reaction step 33.
Reaction step 49: Production of the compound (XXVIII) from the compound (XXVII) This reaction can be conducted by subjecting the compound (X~VII) to the reaction desc.ribed in the reaction step 30.
Reaction step 50: Production of the compound (XXXII) from the compound (X~XI) ~his reaction can be conducted by subjecting the compound (XXXI) to the reaction described in the reaction step 30. And, transformation of the portion A
may be carried out simultaneously by a suitable combination of the reaction described in the reaction step 30 with any one of the reactions described in the reaction steps 9, 10, 13, 14, 17 and 13.
Reaction step 51: Production of the compound (XXXII) from the compound (XXVIII) This reaction can be conducted by subjecting the compound (XXVII) to the reaction described in the reaction step 33.
When substituents such as amino group, lower alkyl amino group, hydroxyl group and carboxyl group are 3~ present on starting compounds to be employed in the afore-described methods and on acylating agents, carbamoylating agents, alkylating agents and sylfonylating agents to be employed in these methods, the reaction can be allowed to proceed advantageously by having these substituents protected previously.
For the protection and deprotection of these ~2~
- 3g -substituents, a per se known method [Greene, T.W., "Protective Group in Organic Synthesis", John Wiley &
Sons, New York (1981)] can be used.
Thus-produced compounA (I) of the present invention can be isolated by, for example, ~ 9e known separating and reining means (e.g. chromatography, crystallization). ~nd, in the case o the compound (I) containing counter anion shown by X~, exchange of the counter anion can be conducted by processing with, for example, ion-exchange resin or silver salt (e.g. silver oxide, silver acetate, silver perchlorate, etc.).
The compounds of this invention show an action of inhibiting angiogenesis and and an anti-tumor activity, and are useful as therapeutic and prophylactic agents of various inflammatory diseases (rheumatic diseases, psoriasis), diabetic retinopathy or tumors, and their toxicity is relatively low. ~nd, they can be safely administered orally or non-orally as they are or as a pharmaceutical composition prepared by mixing with Per se known pharmaceutically acceptable carriers, excipients, etc. [e.g. tablets, capsules (including soft capsules, microcapsules), liquidsr injections, suppositories]. The dosage varies with, among others, subjects, routes and symptoms, but, usually, it ranges, in an adult, from about 0.1 mg/kg to about 40 mg/kg body weight, preferably from about 0.5 mg/kg to about 20 mg/kg body weight per day.
Pharmacological effects of the compounds of this invention are described as follows.
Experimental Example 1 Angiogenesis inhibitory action by the rat cornea micropocket method Method of Evaluation :
Essentially the same method of Gimbrone et al. [J.
National Cancer Institute 52:413-419 (1974)~ was followed.
2 ~ 3 ~ ~) Thus, adult male Spra~ue-Dawley rats (11 to 16 week old) were anesthetized with nembtal and locally anesthetized hy instillation of xylocaine eyedrops onto the eyeball. The cornea was incised to a length of about 2 mm at about 2 mm inside from the corneal c.i.rcumference by means of an injection needle, and a basic fibroblast growth factor (bFGF, bovine brain-derived, purified product, ~ & D Inc.) and a sustained xelease pellet containing the test sample were inserted side by side into the incision so that the bFGF pellet was located on the central side in the cornea. In the control group, the bFGF pellet and a sample-free pellet we.re inserted into the cornea. After 10 days, the cornea was observed under a stereoscopic microscope.
The results are shown in Table 1.
The sustained release pellets were prepared in the following manner. An ethylene-vinyl acetate copolymer (Takeda Chemical Industries, Ltd.) was dissolved in dichloromethane to a concentration of 8%. A 3 ~1 portion of the solution was air-dried on a glass dish, an aqueous solution of bFGF (250 ng) was then placed thereon and air-dried and, finally 3 ~1 of the above-mentioned ethylene-vinyl acetate copol~mer solution was placed further thereon and air-dried to give a sandwich sheet. This sandwich sheet was made round into a bFGF
pellet. The test sample pellets were prepared by dissolving each sample in ethanol to a concentration of 20 ~g/2 ~1, mixing the solution with 6 ~1 of an ethylene-vinyl acetate copol~mer solution, air-drying the mixed solution on a glass dish and making the thus-obtained sheet round.
`` 2 ~
Table 1 Angiogenesis Inhibitory Activity Compound (~xample No.) Inhibitory Rate Judgment lc S/5 4 3/5 +
~8 4/7 Incidentally, in the above Table 1, the numbex of rats subjected to the test was shown by denominator, and the number of rats whose angiotensin due to bFGF
was retarded or weakened by administration of the test sample was shown by numerator. In the judgment, +
means an inhibit.ion rate of 70% or more, and ~ means that of less than 70% but exceeding 40%.
Experimental Example 2 C57BL/6 mice (a group consisting of 6 mice) were inoculated subcutaneously at the dorsolateral area with 2 x 106 M5076 cells, and then a test compound dissolved in a 5% gum arabic physiological saline solution was subcutaneously administered lO times in total, i.e.
1st, 2nd, 4th, 5th, 6th, 7th, 8th, 9th, 11th and 12th day after the inoculation. After 13 days, the major axis (a) and the minor axis ~b) of the tumor tissue were measured to determine the tumor size by the calculation formula of a x b2 x 1/2. The ratio of the tumor size thus calculated to the tumor size of animals in the control group was shown by T/C (~). The results are shown in Table 2.
:
2 ~
~ 42 -Table 2 Compound (Example No.) Dose (mg/kg) T/C(%) lc 30 20 : 15 76 20 29 104 ~0 16 Examples By the following Reference Examples and Examples, the present invention will be described in more detail, but the present invention is by no means limited to these examples.
The elution in the column chromatography in the following Reference Examples and Examples (bracketed terms are solvents for elution) is conducted under observation by means of thin layer chromatography (TLC).
In the TLC observation, as the TLC plate, Kieselgel 60F250 (70 to 230 mesh, Merck) was employed, as the developing solvent, the one employed for elution in the column chromatography, and, as the method of detection, a UV detector, a color-development method with phosphorus molybdate, etc. were employed. As the silica gel for the column, ~ieselgel 60 (70 to 230 ~ a 2 ~
mesh, Merck) ~as employed. NMR spectrum shows proton N~R(IH~NMR), and, as interior or exterior standard, tetramethylsilane was employed, and the measurement was carri.ed out by using Gemini 200 (VARIAN) showing the value in terms of ppm.
Incidentally, abbreviations used in Reference Examples and Examples have the following significances, respectively.
s:singlet, br:broad, d:doublet, dd:double doublet, ddd:doublet doublet doublet, t:triplet, q:quartet, m:multiplet, ABq:AB quartet, J:coupling constant, Hz:Hertz, %:weight %.
And, the term "room temperatures" appearing in the following reference examples and working examples means temperatures ranging from about lS to 25C. Melting points and temperatures are all shown by cent~grade.
In the description of compound names in the following Reference Examples and Examples, portion of the absolute steric configuration was omitted as it was in agreement with that of ft~agillol. Referring to the relative steric configuration, only the portion different from that of fumagillol based on the structural formula shown for Compound (I) was described.
Reference Example 1 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1,4-cyclohexanediol To a solution of fumagillol (200 mg) in ethanol (2 ml) was added 0.5N hydrochloric acid (1 ml), and the mixture was stirred at room temperatures for one hour.
To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate to neutralize, which was concentrated under reduced pressure. The concentrate was purified by means of a silica gel column chromatography (carrier 10 g, developing ~2~i3~
- 44 ~
solvent:hexane-ethylacetate=3:1) to give 2-(1,2-epoxy~
1,5-dimethyl-4-hexenvl)-3-me-thoxy-1-(chloromethyl)-1,4-cyclohexanediol (200 mg: yield 90~).
NMR spectr~m (~ value;CDC~3) : 1.33(1H,m), 1.49(3H,s), 1.67(3H,s), 1.75(3H,s), 1.5 to 2.6(7H,m), 2.99(1H,t,6Hz), 3.2 to 3.4(1H,m), 3.35(3H,s), 3.50(1H,d,llHz), 3.90(1H,br s), 4.23(1H,m), 5.19(1H,m).
Reference Example 2 O chloroacetylcarbamoyl fumagillol To a solution of fumagillol (314 mg) in dichloromethane (5 ml) was added dropwise, under cooling with ice, chloroacetylisocyanate (160 mg), to which was then added dimethylaminopyridine (130 mg), followed by stirring at 0C ~or two hours. To the reaction mixture was added water, which was subjected to extraction with dichloromethane. The organic layer was washed with a saturated aqueous saline solution, then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica ~el colunln chromatography (carrier 20 g, developing solvent: ethylacetate-hexane=1:2) to afford O-chloroacetylcarbamoyl fumagillol (318 mg: yield 71%) as colorless powder.
NMR spectrum (~ value; CDC~3) : l.lO(lH,m), 1.21(3H,s), 1.66(3H,s), 1.75(3H,s), 1.93(1H,d,llHz), 1.8 to 2.5(5H,m), 2.57(1H,d,4Hz), 2.58(1H,m), 2.99(1H,d,4Hz), 3.47(3H,s), 3.58(1H,dd,llHz,3Hz), 4.44(2H,s), 5.20(1H,m), 5.61(1H,m), 8.33(1H,br s).
Reference Example 3 O-(p-toluenesulfonyl)fumagillol To a solution of fumagillol (3.00 g) and dimethylamino pyridine (3.24 g) in anhydrous dichloromethane (30 ml) was added p-toluenesulfonyl , - 2 ~
- 45 ~
chloride (3.04 g), and the mixture was stirred at room temperatures o~ernight. The reaction mixture was diluted with d.ichloromethane, washed with a saturated aqueous saline sol~tion, followed by drying over anhydrous magnesium sul-eate. The solvent WclS d.istilled off under reduced pressure, then the residue was purified by means of a silica gel column chromatography (carrier 150 g, developing solvent:ethyl acetate-hexane=1:2). The resulting crude crystals were recrystallization from diisopropylether to afford O-(p-toluenesulfonyl)fumagillol as colorless crystals (2.88 g : yield 62%). m.p.: 123 to 124C.
NMR spectrum (~ value; CDC~3) : 1.14(1H,m), 1.16(3H,s), 1.67(3H,s), 1.70(3H,s), 1.84(1H,m), 1.95(lH,d,llHz), 2.04 to 2.47(4H,m), 2.44(3H,s) t 2.55(lH,d,4Hz), 2.56(lH,t,6Mz), 2.94(lH,d,4Hz), 3.02(3H,s), 3.50(lH,dd,lOHz),2Hz), 5.07(lH,m), S.l9(1H,m), 7.33(2H,d,8Hz), 7.87(2H,d,8Hz).
Reference Example 4 O-phenoxycarbonyl fumagillol Fumagillol (133 mg) and dimethylaminopyridine ~115 mg) were dissolved in dichloromethane (3 ml). To the solution was added phenyl chloroformate (lll mg), and the mixture was stirred for 30 minutes at room temperatures. To the resultant was added water, which was diluted with dichloromethane (30 ml), followed by washing with water and a saturated aqueous solution of sodium chloride. The solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (carrier 10 g, developing solvent : n-hexane-ethyl acetate=5:1) to afford O-phenoxycarbonyl fumagillol (174 mg : yield 92%) as a colorless oily product.
NMR spectrum (~ value; CDC~3) : l.lO(lH,m), 1.22(3H,s), 1.66(3H,s), 1.75(3H,s), 1.8 to 2.45(6H,m), 2 ~J~'~ 3 ~3'X
2.56(1~,d,4Hz), 2.59(1H,-t,6Hz), 2.99(1H,d,4Hz), 3.50(3H,s), 3.69(1H,dd,llHz,3~Iz), 5.18(1H,m), 5.58(1H,br s), 7.15 to 7.45(5H,m).
Reference Example 5 6-O-formyl-6-epifumagillol F~lmagillol ~4.0 ~), triphenylphosphine (11.2 g) and formic acid (1.1 ml) were dissolved in tetrahydrofuran (100 ml). To the solution was added dropwise a solution of diethylazocarboxylate ~7.4 g) in tetrahydrofuran (20 ml). The mixture was stirred overnight, which was then diluted with eth~l acetate (300 ml), followed by washing with a saturated a~ueous solution of sodium chloride, then with a saturated aqueous solution of sodium hydrogencarbonate and further with a saturated aqueous solution of sodium chloride. The resultant was dried over anhydrous magnesium sulfate, then the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel chromatography (carrier 200 g, developing solvent : ethyl acetate-he~ane = 1:3) to af~ord 6-O-formyl-6-epifumagillol (2.6 g: yield 59%).
NNR spectrum (~ value; CDCQ3): 1.21(1H,m), 1.27(3H,s), 1.61(1H,d,llHz), 1.66(3H,s), 1.75(3H,s), 1.70 to 2.25(4H,m), 2.38(1H,m), 2.56(lH,m), 2.59(1H,d,4Hz), 2.98(1H,d,4Hz), 3.56(3H,s), 3.83(lH,dd,9Hz,llHz), 5.00(lH,m), 5.20(lH,m), 8.17(1H,s).
Reference Example 6 6-Epifumagillol - 6-O-formyl-6-epifumagillol (2.5 g) was dissolved in methanol (20 ml), to which was added conc.
ammoniacal water (5 ml), and the mixture was stirred for 15 minutes. The solvent was distilled o~f under reduced pressure, then the residue was dissolved in 2~2~
ethyl acetate (100 ml), which was washed with a saturated aqueous solution of sodium chloride. The resultant was dried over anhydrous ma~nesium sulfate, thell the solvent was distilled off under reduced pressure. The res.idue was puri~ied by means o a silica gel chromatoc3raphy (carrier 100 g, developing solvent : ethyl acetate-hexane = 2:1) to afford 6-epifumagil]ol (1~8 g: yield 79%).
NMR spectrum (~ value; CDCR3): 1.22(1~,m), 1.30(3H,s), 1.54(1H,d,11Hz), 1.66(3H,s), 1.75(3H,s), 1.70 to 2.25(4H,m), 2.38(1H,m), 2.54(1H,d,4Hz), 2.57(1H,t,7Hz), 2.91(1H,d,4Hæ), 3.54 to 3.80(2H,m), 3.61(3H,s), 5.20(1H,m).
Reference Example 7 6-0-phenoxycArbonyl-6-epifumagillol 6-Epiumagillol (0.53 g) and dimethylaminopyridine (0.46 g) were dissolved in dichlorom~thane (8 ml), to which was added phenyl chloroformate (0.45 g), followed by stirring at room temperatures for 30 minutes. To the resultant was added water, which was then diluted with dichloromethane (40 ml). Th0 resultant was washed with water and a saturated aqueous solution of sodium chloride, which was dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel chromatography (carrier 2S g, developing solvent : ethyl acetate - hexane = 1:5), followed by crystallization from ethanol to give 6-O-phenoxycarbonyl-6-epifumagillol (0.55 g; yield 82%).
m.p. 118 to 119C
NMR spectrum (~ value; CDC23) : 1.22(1H,m), 1.28(3H,s), 1.63(1H,d,llHz), 1.66(3H,s), 1.75(3H,s), 1.6 to 2.5(5H,m), 2.57(1H,t,7Hz), 2.59(1H,d,4Hz), 2.98(1H,d,4Hz), 3.65(3H,s), 3.84(1H,dd,9Hz,llHz), 4.88(1H,m), 5.20(1H,m), 7.1 to 7.5(5H,m).
~ ~ 2 ~
- ~8 -Reference Example 8 6-O-morpholinocarbonyl ~-epi.f~lmagillol 6-O-phenoxycarbon~1-6-epifumagillol (0.17 g) was dissolved in dichloromethane (~ ml), to which was added morpholine (1 ml), and the mixture was stirred at room temperatures for one day. The reaction mixture was diluted with ethyl acetate (30 ml), which was washed with a saturated aqueous solution of ammonium chloride and a saturated aqueous solutio~ of sodium chloride.
The resultant was dried over magnesium sulfate, then the solvent was distilled off under reduced pressure.
The residue was purified by means of a silica gel chromatography (carrier 20 g, developi~g solvent :
ethyl acetate - hexane - 1:2) to afford 6-O-morpholinocarbonyl-6-epifumagillol (0.13 g : yield 74%). m.p. : 139 to 1~0C
NMR spectrum (~ ~alue; CDC23): 1.20(1H,m), 1.26(3H,s), 1.66(3H,s), 1.75(3H,s), 1.6 to 2.6(7H,m), 2.58(1H,d,4Hz), 2.97(1H,d,4Hz), 3.50(4H,m), 3.54(3H,s), 3.67(4H,m), 3.80(1H,dd,9Hz,llHz), 4.87(1H,m), 5.~1(lH,m).
ReferPnce Example 9 6~-Phthalimido-6-desoxyfumagillol Fumagillol (1.0 g), triphenylphosphine (1.22 g) and phthalimide (0.57 mg) were dissolved in tetrahydrofuran (THF, 30 ml), to which was added dropwise a solution of diethyl azodicarboxylate (0.83 g) in THF (5 ml). The mixture was stirred ~or 30 minutes, which was then diluted with ethyl acetate (100 ml). The resultant was washed with a saturated aqueous solution of sodium chloride, then with a saturated aqueous solution of sodium carbonate and, further, with a saturated aqueous solution of sodium chloride once again, followed by drying o~er anh~drous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (carrier 50 g, developillg solvent : ethyl acetate-hexane=1:3) to afford 6~-phthalimido-b-desoxyfumagillol (0.99 g: yield 68%).
NMR spectrum (~ value; CDCQ3): 1.27(lH,m), 1.32(3H,s), 1.65 to 2.70(7H,m), 1.67(3H,s), 1.73(3H,m), 2.58(1H,d,4Hz), 2.99(1H,d,4Hz), 3.33(3H,s), 4.36(1H,m), 4.71(lH,t,lOHz), 5.23(lH,m), 7.73(2H,m), 7.83(2H,m).
Reference Example 10 6~-Amino-6-6-desoxyfumagillol 6~-Phthalimido-6-desoxyfumagillol (2.0 ~) was dissolved in methanol (40 ml), to which was added hydrazine-hydrate (1.4 g), and the mixture was stirred for 20 minutes. The solvent was distilled off under reduced pressure, and the residue was subjected to azeotropic distillation with ethanol to remove the excess amount of hydrazine-hydrate. The residue was dissolved in water (20 ml), to which was added acetic acid (1.5 ml), and the mixture was stirred overnight.
Resulting precipitates were filtered of~. To the filtrate was added conc. ammoniacal water (4 ml), then the product was extracted with chloroform. The extract solution was dried over anhydrous magnesium sulfate, then the sol~ent was distilled off under reduced pressure. The residue was purified by means of a silica g~l column chromatography (carrier lO0 g, developing solvent: chloroform-methanol-conc.
ammoniacal water=30:1:0.03) to afford 6~-amino-6-desoxyfumagillol (0.9 g: yield 40%).
NMR spectrum (~ value; CDCQ3): 1.17(1HIm), 1.29(3H,s), 1.50 to 1.95(4H,m), 1.66(3H,s), 1.79(3H,m), 2.27(1H,m), 2.37(1H,m), 2.52(1H,d,4Hz), 2.55(1H,t,6Hz), 2.90(1H,m), 2.92(1H,d,4Hz), 3.47(1H,dd,9Hz,llHz), ~ ~ 2 !~ J ~3 ;~
-- so 3.S6(3H,s), 5.22(lH,m).
Reference Example 11 6~-Hexylamino-6-desoxy~umagillol 6~-~mino-6-desoxyfumagillol (3.0 ~), hexanal (1.4 ml) and acetic acid (l.S ml) were dissolved in methanol (60 ml). ~o the solution was added sodium cyanoborohydride (0.67 g). The mixture was stirred for one hour, and the resulting reaction mixture was diluted with ethyl acetate (100 ml), followed by washing with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodi.um chloride. The resultant was dried over anhydrous ~agnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of a silica gel column chromatography (carrier 150 g, developing solvent: chloroform-methanol-conc. ammoniacal water=30:1:0.03) to afford 6~-hexylamino-6-desoxyfumagillol (2.35 g: yield 60%).
NMR spectrum (~ value; CDC~3): 0.89(3H,m), 1.10 to 2.35(12H,m), 1.66(3H,s), 1.74(3H,m), 2.51(1H,d,4Hz), 2.92(1H,d,4Hz), 3.50(3H,s), 3.69(1I~,dd,9Hz,llHz), 5.22(lH,m).
Reference Example 12 2-(1,2-epoxy-1,5-dimethyl-~-hexenyl)-3-methoxy-1-methylthiomethyl-4-oxo-1-cyclohexanol 6-Oxo-6-desoxyfumagillol (870 mg) was dissolved in DMF (2 ml), to which was added thiomethoxide (652 mg).
The mixture was stirred for 30 minutes, followed by addition of water thereto to suspend the reaction. The product was extracted with isopropylether. The extract solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, which was then dried over anh~drous magnesium sulfate. The solvent was distilled off under - 51 - ~ ~2~3~
reduced pressure. The residue was purified by means of a silica gel column chromatography (carrier 50 g, developing solvent: eth~l acetate-hexane=1:2) to afford 2-~1,2-epoxy-1,5-dimethyl-~-hexenyl)-3-methoxy-4-oxo-1-methylthiomethyl-l-cyclohexanol (693 mg: yield 70%).
NMR spectrum ~ value; CDC~3): 1~46(3H,s), 1.67~3H,s), 1.75(3H,s), 1.88(1H,m), 2.05 to 2.60(4H,m), 2.20(3H,s), 2.30(1H,d,12Hz), 2.80(1H,m), 2.91(1H,d,13Hz), 2.99(1H,d,13Hz), 3.30(1H,t,6Hz), 3.41(3H,s), 3.~8(1H,d,12Hz), 5.20(1H,m).
Example la 2 (1,2-Epoxy-1,5-dimethyl-4~hexenyl)-3-methoxy-1-bromomethyl 1,4-cyclohexanediol To a solution of fumagillol (230 mg) in ethanol (2 ml) was added a 5~ aqueous solution of hydrobromic acid (1 ml), and the mixture was s~irred ~ox one hour at room temperatures. The reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, followed by concentration under reduced pressure. The concentrate was purified by means of a silica gel column chromatography (carrier 10 g, developing solvent: hexane-ethyl acetate=7:3) to afford 2-(1,2-epoxy-1,5-dimethyl~4--hexenyl)-3-methoxy-1-bromome~hyl-1,4-cyclohexanediol (242 mg: yield 80~) as a colorless oily product.
NM~ spectrum (~ value; CDCR3): 1.40(1H,m), 1.50(3H,s), 1.67(3H,s), 1.74(3H,s), 1.5 to 2.6(7H,m) 3.00(1H,t,6Hz), 3.2 to 3.4(1H,m), 3.35(3H,s), 3.49(1H,d,lOHz), 3.70(1H,d,lOHz), 3.90(1H,br g~, 4.22(lH,m), 5.19(lH,m).
Example lb 2-(1,2-Epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-iodomethyl-1,4-cyclohexanediol Sodium iodide (398 mg) and sodium acetate (36.3 mg) were dissolved in a mixture of acetic acid (0.5 ml) and propionic acid (1 ml). To the solution was added, under ice-cooling, ~umagillol (500 mg). The mixture was stirred for 20 minutes, which was then poured into a conc. ammoniacal water (l0 ml) to suspend the reaction. The product was e~tracted with ethyl acetate. The extract solution was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (carrier 20 g, developing solvent: ethyl acetate-he~ane=1:2), followed by crystallization ~rom isopropylether to afford 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-iodomethyl-1,4-cyclohexanol (667 mg: yield 92%) as colorless crystals, m.p. 86 to 88C.
NMR spectrum (S value; CDC~3): 1.48(1H,m), 1.51(3H,s), 1.67(3H,s), 1.75(3H,s), 1.70 to 2.55(6H,m), 3.01(1H,t,7Hz), 3.26(1H,m), 3.35(3H,s), 3.50(1H,d,lOHz), 3.57(1H,d,lOHz), 4.20(1H,m), 5.19(lH,m).
Bxample lc 4-O-(Chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-l-chloromethyl-l~4-cyclohexanedi To a solution of O-(chloroacetylcarbamoyl)-fumagillol (100 mg) in methanoI (2 ml) was added 0.4N
hydrochloric acid (1 ml), which was stirred for one hour at room temperatures. Resulting precipitates were collected by filtration and recrystallized from methanol-water to afford 4-O-(chloroacetylcarbamoyl)~2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1,4-cyclohexanediol (96 mg, yield 90%) as colorless crystals.
NMR spectrum (~ ~alue; CDC~3): 1.43(1H,m), 1.50(3H,s), 1.74(3H,s), 1.5 to 2.6(6H,m), 1.95(1H,t,6Hz), 3.30(1~,m), 3.32(3H,s), 3.49(1H,d,llHx), 3.87(1H,d,llHz), 4.12(1H,br s), 4.52(2H,s), 5.18(1H,m), 5.45(1H,m), 8.06(1H,br s).
Example 2 4-O-(Acryloylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1,4-cyclohexanediol To a solution of 2-(1,2-epoxy-l,S-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1,4-cyclohexanediol (418 mg) in dichloromethane (5 ml) was added dropwise acryloylisocyanate (300 mg). The mixture was stirred for 30 minutes at room temperatures. To the reaction mixture was added water, which was subjected to extraction with ethyl acetate. The extract solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (carrier 20 g, developing solvent: hexane-ethyl acetate=4:1) to afford 4-O-(acryloylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-l-chloromethyl-lr4-cyclohexanedi (200 mg, yield 38%) as colorless crystals.
NMR spectrum (~ value; CDCR3): 1.50(3H,s3, 1.66(3H,s), 1.74(3H,s), 1.35 to 2.6(7H,m), 2.96(1H,t,7Hz), 3.30(1H,m), 3.33(3H,s), 3.48(1H,d,llHz), 3.87(1H,d,llXz), 4.12(1H,br s), 5.18(lH,m),5.45(lH,m), 5.91(lH,dd,llHz,2Hz), 6.55(1H,dd,17Hz,2Hz), 7.08(1H,dd,17Hz,l].Hz), 7.64(1H,br s ) .
Example 3 4-O-(methacryloylcarbamoyl)-2-~1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1,4-cyclohexanediol - 54 - 2~2l~3 Likewise in Example 2, a mixture of 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1,4-cyclohaxanediol (1.13 g) and methacryloylisocyanate (800 mg) was stirred for 30 minut~s at room temperatures. 'rhe reaction mixtu.re was puri~ied by means o~ ~ silica gel column chromatography (carrier 50 g, developing solvent:hexane-ethyl acetate=3:1) to a~ford 4-O-(methacryloylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3 methoxy-1-chloromethyl-1,4-cyclohexanediol (520 mg, yield 34~) as colorless crystals.
NMR spectrum (~ value; CDC~3) : 1.51(3H,s), 1.66(3H,s), 1.74(3H,s), 2.02(3H,s), 1.2 to 2.6(7H,m), 2.97(1H,t,6Hz), 3.3 to 3.4(1H,m), 3/34(3H,s), 3.54(1H,d,llHz), 3.86(1H,d,llHz), 4.11(1H,br s), 5.18(1H,m), 5.50(1H,d,3Hz), 5.60(1H,d,2Hz), 5.78(1H,s), 7.81(1H~S)-Example 4 4-0-(3-Chloro-2-methyl-propionylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1,4-cyclohexanediol Likewise in Example 2, 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-l-chloromethyl-ll4~cyclohexanedi (1.13 g) and methacryloylisocyanate (800 mg) were stirred for 30 minutes at room temperatures. The resultant product was purified by means of a silica gel column chromatography (carrier 50 g, developing solvent:hexane-ethyl acetate=4:1) to a~ford 4-0-(3-chloro-2-methyl-propionylcarbamoyl)~2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1,4-cyclo-- hexanediol (281 mg, yield 17%) as colorless crystals.
NMR spectrum (~ value;CDCQ3): 1.31(3H,d,7Hz), 1.50(3H,s), 1.75(3H,s?, 1.2 to 2.55(7H,m), 2.97(1H,t,6Hz), 3.33(3H,s), 3.49(1H,d,llHz), 3.87(lH,d,llHz), 3.25 to 4.3(4H,m), 4.11(lH,br s), 2 ~
- ss -5.18(lH,m), 5.45(lH,d,3Hz), 7.82(lH,br s).
Example 5 4-O-Phenylthioace-tylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-phenylthiomethyl 1,4-cyclohexanediol To a solution o~ O-chloroacetylcarbamoylfu~lagillol (122 mg) in ~MF (2 ml) was add~d thiophenol.sodium salt (400 mg), and the mixture was stirred for 30 minutes at room temperatures. The reaction mixture was diluted with ethyl acetate, and the organic lay~r was washed with water and a saturated aqueous saline solution, followed by drying over magnesium sulfate. The solvent was distilled off under reduced pressure, then the residue was puri~ied by means o~ a silica gel column chromatography (carrier 10 ~, developing solvent:hexane-ethyl acetate=5:1) to afford 4-O-(phenylthioacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-phenylthiomethyl-1,4-cyclohexanediol (181 mg, yield 99%) as colorless powder.
NMR spectrum ~ value; CDCQ3): 1.45(3H,s), 1.65(3H,s), 1.72(3H,s), 1.2 to 2.5(7H,m), 2.96(lH,t,7Hz), 3.31(3H,s), 3.39(3H,m), 3.98(1H,d,14Hz), 4.00(1H,br s), 4.08(1H,d,14Hz), 5.18(1H,br s,7Hz), 5.44(1H,br s), 7.1 to 7.5~10H,m), 8.29(1H,br s).
Example 6 4-O-(l-naphthylthioacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-(1-naphthylthiomethyl)-1,4-cyclohexanediol Likewise in Example 5, O-chloroacetylcarbamoyl ~umagillol (129 mg) and 1-naphthylthiol.sodium salt (302 mg) were stirred for 10 minutes at room temperatures, and the resultant was puri~ied by means 2 ~
of a silica gel column chromatography (carrier 10 ~, developin~ solvent:hexane-ethyl acetate=4:1) to afford 4-O-(1-naphthylthioacetylcarbamoyl)-2-(1,2-epoxy-l,S-dimethyl-4~hexenyl)-3-methoxy-1-(1-naphthylthiomethyl)-1,4-cyclohexanediol (207 mg, yi~ld 94%) as colorless po~,7der.
NMR spectrum (~ value; CDC~3): 1.46(3H,s), 1.64(3H,s), 1.72(3H,s), 1.2 to 1.95(4H,m), 2.05 to 2.55(3~,m), 2.96(1H,t,6Hz), 3.11(3H,s), 3.2 to3.4(1H,m), 3.40(1H,d,13Hz), 3.43(1H,d,13Hæ),4.02(1~,d,15Hz), 4.05(1H,br s), 4.13(1H,d,15Hz), 5.17(1H,m), 5.42(1H,m), 7.3 to 7.95(13H,m), 8.44(2H,m).
Example 7 4-0-(8-Quinolylthioacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-(8-quinolylthiomethyl)-1,4-cyclohexanediol Likew~se in Example 5, O-chloroacetylcarbamoyl fumagillol (119 mg) and 8-mercaptoquinoline.sodium salt (357 mg) were stirred for 30 minutes at room temperatures.
The resultant product was purified by means of a silica gel column chromatography (carrier 10 g, developing solvent:hexane-ethyl acetate=7:3) to af~ord 4-0-(8-quinolylthioacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)~3-methoxy-1-(8-quinolylthiomethyl)-1,4-cy-clohexanediol (181 mg, yield 89~) as colorless powder.
NMR spectrum (~ value; CDC~3): 1.48(3H,~), 1.82(3H,br s), 1.93(3H,br s), 1.2 to 2.6(7H,m), 2.97(1H,m), 3.39(3H,s), 3.3 to 3.6(3H,m), 3.93(1H,d,15Hz), 4.01(1H,d,15Hz), 4.28(1H,br s), 5.12(lH,m), 5.56(lH,m), 7.4 to 7.95(8H,m), 8.1 to 8.25(2H,m), 8.86(1H,m), 9.I7(1H,dd,4Hz,2Hz), 10.94(1H,br s).
~ ~ ~ f~
Example 8 4-O-carbamoyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-(~-quinolylthiomethyl~1,4-cyclohexanediol Likewise in Example 5, O-carbamo~l fumagillol (200 mg) and ~-mercaptoquinoline.sodium salt (300 mg) were stirred for one hou~ at room temperatures. The resultant product was purified by means of a silica gel column chromatography (carrier 10 g, developing solvent: hexane - ethyl acetate=1:2) to afford 4-O-carbamoyl-2-(1,2-epoxy-1,5-dimethyl--4-hexenyl)-3-meth-oxy-1-(8-~uinol~lthiomethyl)-1,4-cyclohexanediol (233 mg, yield 78~) as colorless powder.
NMR spectrum (~ value; CDC~3): 1.48(3H,s), 1.62(6H,br s), 1.2 to 2.6(7H,m), 2.95(1H,m), 3.39(3H,s), 3.3 to 3.4(2H,m), 3.47(1H,d,12Hz), 4.26(1H,m)t 4.79(1H,br s), 4.85(2H,br s), 5.15(1H,br s), 5.39(1H,m), 7.4 to 7.5(2H,m), 7.55 to 7.8(2H,m), 8.18(1H,d,8Hz), 8.95(1H,dd,4Hz,2Hz).
Example 9 4-O-Carbamoyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol To a solution of O-chloroacetylcarbamoyl fumagillol (209 mg) in ethanol (2 ml) was added a 15%
aqueous solution of methanethiol.sodium salt (500 ~1), and the mixture was stirred ror one hour at room temperatures. The reaction mixture was concentrated, to which was added ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (carrier 10 g, developing solvent: hexane-ethyl acetate=2:1) to afford 4-O-carbamoyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-l-methylthiomethyl-1,4-cyclohexanediol (136 mg:
yield 70%) as colorless powder.
NMR spectrum (~ value; CDC~3~: 1.48(3H,s), 1.67(3H,s), 1.74(3I-I,s), 1.2 to l.9(5H,m), 2.18(1H,m), 2.21(3H,s), 2.46(]H,m), 2.85(1H,d,14Hz), 2.96(1H~m), 2.98(1H,d,14Hz), 3.31(1H,m), 3.33(3H,s), 4.71(2H,br s), 5.20(lH,m), 5.33(1~I,m).
Example 10 2-(1,2-Epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol Fumagillol (3.00 g) was dissolved in DMF (6 ml), to which was added thiomethoxide (2.23 g). The mixture was stirred for 30 minutes, to which was added water to suspend the reaction. The product was extracted with isopropylether. The extract solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, then the residue was purified by means of a silica gel column chromatography (carrier 150 g, developing solvent :
ethyl acetate - hexane = 1:2), followed by recrystallization from hexane to afford 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (2.43 g : yield 69~) as colorless powder, m.p. 52 to 53C.
NMR spectrum (~ value; CDC~3): 1.45(3H,s), 1.55(1H,m), 1.66(3H,s), 1.74(3H,s), 1.65 to 1.90(4H,m), 2.08 to 2.55(2H,m), 2.80 to 3.02(3H,m), 3.30(1H,m), 3.35(3H,s), 4.22(1H,m), 5.19(lH,m).
[ ~26 57 5o (c 0.20, CHC~3) Elemental analysis : Cl7H30O4S
Calcd. C:61.78%, H:9.15%, Found C:61.66%, H:9.30~.
Example 11 59 2~2~¢~; ~
4-O-Acetyl-2-(1,2-epox~-:L,5-dimethyl-4-hexenyl)-3-methoxy-l-methylthiomethyl-1,4-cyclohexanediol In dichloromethane (5 ml) was dissolved 2-(1,2-epoxy-1,5-dimethyl~4-hexenyl)-3-methoxy-l~methylth-iomethyl-1,4-cyclohexanediol (620 mg). To the solution were added dimethylaminopyridi.ne (252 m~) and acetic anhydride (0.20 ml), then the mixture was stirred for one hollr. The reaction mixt~re was diluted with ethyl acetate (70 ml), which was washed with water, a 10%
aqueous solution o~ citric acid and a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (carrier 30 g, lS developing solvent: ethyl acetate - hexane = 1:2), ~ollowed by crystallizatio~ ~rom hexane to af~ord 4-O-acetyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-l-methylthiomethyl-1,4-cyclohexanediol t730 mg: yield 100%) as colorless crystals, m.p. 73 to 74C.
NMR spectrum (~ value; CDC~3): 1.48(3H,s), 1.66(3H,s), 1.74(3H,s), 1.60 to 1.90(4H,m), 2.00 to 2.55(3H,m), 2.12(3H,s), 2.21(3H,s), 2.85 to 3.00(3H,m), 3.29(3H,s), 3.34(1H,m), 5.20(1H,m), 5.47(1H,m).
[a]D6-71~8 (c 0.22, CHC~3).
Elemental analysis : C1~H32O5S
Calcd. C:61.26%, H:8.66%, Found C:61.35%, H:8.86.
Example 12 4-O-(Chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol In dichloromethane (lS ml) was dissolved 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-5-methoxy-l-methylth-iomethyl-1,4-cyclohexanediol (1.50 g). To the solution was added dropwise, under ice-cooling, chloroacetyl - 60 - ~ ~2'~3~
isocyanate (0.46 ml). The mixture was stirred ~or 20 minutes, which was diluted with ethyl acetate (60 ml) and washed with a saturated aqueous solution of sodium hydrogencarbonate and a sa~urated aqueous saline sol~ltlon, Eollowed by drying over anhydrous ma~nesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by mearls of a silica gel column chromato~raphy (carrier 75 g, developing solvent : ethyl acetate - hexane = 1:2), followed by crystallization from ether-hexane to afford 4-O-(chloroacety]carbamoyl)-2~(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (1.70 g: yield 83%) as colorless crystals, m.p. 101 to 102C.
NMR spectrum (~ value; CDC~3): 1.46(3H,s), 1.66(3H,s), 1.74(3H,s), 1.60 to 1.92~4H,m), 2.05 to 2.55(3H,m), 2.21(3H,s), 2.84(1H,d,13Hz), 2.93(lH,t,7Hz), 2.99(lH,d,13Hz), 3.32(3H,s), 3.34(lH,m), ~.51(2H,s), 5.19(1~,m), 5.45(lH,m).
[~26 81 5 (c 0.20,CHCQ3).
Elemental analysis for CZoH32No6scl :
Calcd. C:53.38%, H:7.17%, N:3.11%
Found C:53.34%, H:7.14~, N:3.03%
Example 13 4-O-(Chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5 dimethyl-4-hexenyl)-3-methoxy-1-dimethylsulfoniomethyl-1,4-cyclohexanediol iodide In acetonitrile (2 ml) was dissolved 4~0-(chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-h-exenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (500 mg~. To the solution was added methyl iodide ~0.82 ml), and the mixture was stirred for 8 hours. The solvent was distilled off under reduced pressure. The residue was pulverized by the addition of ether to afford 4-O-(N-chloroacetyl-- 61 ~
carbamoyl)-2-(1,2-epoxy-1,5-dimethyl-~-hexenyl)-3-methoxy-l-dimethylsulfoniomethyl-1,4-cyclohexanediol iodide (701 m~: yield 100~) as pale yellow powder.
NMR sp~ctrum (6 vallle; CD~OD): 1.47(3H,s), 1.69(3H,s), 1.75(3H,s), 1.65 to 1.95(4H,m), 2.10 to 2.60(3H,m), 3.01(3~1,s), 3.07(3H,s), 3.12tlH,t,6Hz), 3.46(1H,m), 3.70(1H,d,13Hz), 4.03(2H,s), 4.05(lH,d,13Hz), 5.24(lH,m), 5.48(lH,m).
[~]D6-49.o (c 0.20, CHCQ3).
Elemental analysis for C2lH35NO6SCII.4H2O:
Calcd. C:37.99%, N:2.11%, Found C:38.07~, N:2.16%
Example 14 4-O-acetyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-l-dimethyls~llfoniomethyl-1,4-cyclohexanediol iodide Likewise in Example 13, 4-acetoxy-2-~(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-dimethyl-sulfoniomethyl~l,4-cyclohexanediol iodide (558 mg:
yield 82%) ~as obtained as pale yellow powder from 4-O-acetyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-l-methylthiomethyl-1,4-cyclohexanediol (490 mg).
NMR spectrum (~ value; CD30~): 1.46(3H,s), 1.69(3H,s), 1.75(3H,s), 1.65 to 1.85(4H,m), 2.05 to 2.60(3H,m), 2.08(3H,s), 2.98(3H,s), 3.06(3H,s), 3.12(1H,t,6Hz), 3.30(3H,s), 3.44(1H,m), 3.74(1H,d,13Hz), 4.03(1H,d,13Hz), 5.24(1H,m), 5.51(lH,m).
[a]D6-58.6 (c 0.22, CHC~3).
Example 15 4-O-(Chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-ethylmethylsulfoniomethyl-1,4-cyclohexanediol iodide Likewise in Example 13, 4-O-(chloroac~tyl-~ .J~
carbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-ethylmethylsulfoniomethyl-1,4-cyclohexanediol iodide (59 mg: yield 44~) was obtained as pale yellow powder from 4-O-(chloroacetylcarbamoyl)-2-(1,2-epoxy-S 1,S-dimethyl-4-hexenyl)-3-methoxy-1-meth~lthiomethyl-1,4-cyclohexanediol (150 mg).
NMR spectrum (~ value; CD30D): 1.35 tol.5Q(6H,m), 1.69(3H,s), 1.75(3H,s), 1.65 to 1.95(4H,m), 2.05 to 2.60(3H,m), 2.97(1.5H,s), 3.06(1.SH,s), 3.12(1H,m), 4.03(2H,m), 4.45(1H,m), 5.25(lH,m), 5.45(lH,m).
[~]D6-62.7 (c 0.22, CHCR3).
Eleme~tal analysis for C22H37NO6SClI :
Calcd. C:43.61%, H:6.15~, N:2.31%, Found C:43.83%, H:6.19%, N:2.39~.
Example 16 4-O-(N-chloroacetylcarbamoyl)-2-(1,2-epoxy-l,S-dimethyl-4-hexenyl)-3-methoxy-1-benzylmethylsulfoniomethyl-1,4-cyclohexanediol bromide Likewise in Example 13, 4-O-(N-chloroacetyl-carbamoyl)-2 (1,2-epoxy-l,S-dimethyl-4-hexenyl)-3-methoxy-l-benzylmethylsulfoniomethyl-1,4-cycl-ohexanediol bromide (152 mg: yield 73~) was obtained as colorless powder from 4-O-~N-chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5 dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (150 mg).
NMR spectrum (~ value; CD30D): 1.42(3H,m), 1.68(3H,s), 1.65 to 2.00(4H,m), 2.10 to 2.60(3H,m), 2.82(1.5H,s), 3.00(1.5H,s), 3.12(1H,m), 3.30 to 3.75(8H,m), 4.03(lH,m), 4.45 to 5.05(4~,m), 5.25(lH,m), 5.45(1H,m).
[a]D6-43.0 (c 0.22, CHC~3).
Elemental analysis for C27H39NO6SBrCl-2-5H2O :
Calcd. C:48.69%, H:6.66%, N:2.10~
Found C:48.66%, H:6.35%, N:2.29%.
- 63 - 2~ J
Example 17 ~-O-(Chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-(2-propinyl)-methylsulfoniomet}lyl-1,4-cyclohexanediol bromide L.ikewise in Example 13, ~rom 4~0-(chloroacQtyl-carbamoyl)~2-(1,2-epoxy-l,S-dimethyl-4-hexenyl)-3-methoxy-l-methylthiomethyl-1,4-cyclohexanediol (150 mg) was obtained 4~0-O-~chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy~ 2-p~opinyl)methylsulfoniomethyl-1,4-cyclohexanediol bromide (97 mg: yield 51%) as pale yellow powder.
NMR spectrum (~ value; CD30D): 1.40(1.5H,s), 1.45(1.5H,s), 1.68(3H,s), 1.74(3H,s), 1.65 to 2.00(4H,m), 2.10 to 2.60(3H,m), 2.90 to 3.90(9H,m), 4.18(2H,m), 4.44(lH,s), 5.25(lH,m), 5.45(lH,m).
~a]26-43.0 (c 0.20, CHC~3).
Elemental analysis for C23H35NO6SBrCl:
Calcd. C:48.55%, H:6.20%, N:2.46%, Found C:48.48% H:6.21%, N:2.59%.
Example 18 4-O-(l-Naphthyl)carbamoyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-5-methoxy-1-methylthiomethyl-1,4-cyclohexanediol - 25 Likewise in Example 12, 4-O-(l-naphthyl)carbamoyl~
2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-5-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (378 mg: yield 83%) was obtained as colorless powder from 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthi-omethyl-1,4-cyclohexanediol (300 mg).
NMR spectrum (~ value; CDC3): 1.45(3H,br s), 1.67(3H,s), 1.75(3H,s), 1.65 to 2.00(4H,m), 2.05 to 2.55(3HIm), 2.17(3HIbr s), 2.75 to 3.05(2H,m), 3-32(lH~m)~ 3-37(3H,m), 5.21(1H,m), 5.51(lH,m), 7.44 to 8.00(7H,m) [~]~6-85.5O (c 0.22, CHC~3).
2 ~2'~
Example 19 ~-O-(l-Naphthyl)carbamoyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-di.me-thylsulfoniomethyl-1,4-cyclohexanediol iodide Likewise in Example l3, from 4-O-(l-naphthyl)-carbamoyl-2-(1,2-epoxy-1,5-dimethyl-~-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (150 mg) was obtained 4-O-(1 naphthyl)carbamoyl-2-(1,2-epoxy-1,S-dimethyl-4-hexenyl) 3-methoxy-1-dimethyl-sulfoniomethyl-1,4-cyclohexanediol iodide (177 mg:
yield g2%) as pale yellow powder.
NMR spectrum (~ value; CD30D): 1.44(3H,br s), 1.69(3H,s~, 1.76(3H,s), 1.70 to 2.00(4H,m), 2.10 to 2.60(3H,m), 2.98(3H,s), 3.06(3H,s), 3.12(1~1,m), 3.39(3H,s), 3.45(2H,m), 4.02(1~,m), 5.27(lH,m), 5.45(lH,m).
[~26 51 0 (C O . 22, CHC~3).
Elemental analysis for C29H4ONO5SI :
Calcd. C:54.29~, H:6.28%, N:2.18~, Found C:54.17%, H:6.35~, N:2.08%
Example 20 4-0-(2-benzothiazoyl)thioacetylcarbamoyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-dimethylsulfoniomethyl-1,4-cyclohexanediol iodide In methanol (1 ml) was dissolved 4-O-(chloro-ace~ylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-dimethylsulfoniome'hyl-1,4-cyclohexanediol iodide (200 mg). To the solution was added 2-mercaptobenzothiazol.sodium salt (127 mg), and the mixture was stirred for 30 minutes. The reaction mixture was diluted with ethyl acetate (70 ml), then washed with water, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution,followed by drying over anhydrous - 65 - 2 ~
magnesium sulfate. The solvent was distilled off under reduced pressure, then the residue was purified by means of a sillca gel column chromatography tcarrier 10 g, developing solvent: chloroform-methanol=10:1) to afford ~-0-(2~benzothiazoyl)thioacetylcarbamoyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-metho~y l-dimethyl-sulfoniomethyl-1,4-cyclohexanediol iodide (65.8 mg:
yield 26%) as colorless powder.
NMR spectrum (~ value: CD3QD): 1.48(3H,s), 1.6~(3H~s), 1.73(3H,s), 1.65 to 1.90(5H,m), 2.00 to 2.55(2H,m), 2.96(1H,m), 3.06(3H,s), 3.20(1H,m), 3.27(3H,s), 3.31(3H,s), 3.81(1H,d,14Hz), 4.40 to 4.70(3H,m), 5.i4(lH,m), 5.42(lH,m), 7.25 to 7.50(2H,m), 7.15(1H,d,7H2), 7.89(1H,d,8Hz).
[a]26-4.7 (c 0.10, CHCQ3).
E~ample 21 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-phenylthiomethyl-1,4-cyclohexanediol To methanol (5 ml) was added, under ice-cooling, 60% sodium hydride (213 mg), and the mixture was stirred for 5 minutes at room temperatures, to which was then added thiophenol (0.55 ml), followed by stirring for 15 hours. To the resultant mixture was added fumagillol (500 mg), which was stirred for 30 minutes, followed by adding water to suspend the reaction. The product was extracted with ethyl acetate, and the extract solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure r and the residue was purified by means of a silica gel column chromatography (carrier 25 g, developing solven~: ethyl acetate-hexane = 1:2), followed by crystallization from isopropylether to afford 2-(1,2-epoxy-1,5-dimethyl-4-- 66 - 2~2~30~
hexenyl)-3-methoxy-l-phenylthiomethyl-ll4-cyclohexanediol (660 mg: yield 95%) as colorless crystals, m.p. 94 to 96C.
NMR spectrum (~ vallle; CDCR3): 1.45(3H,s), 1.45 to 1.95(4H,m), 1.66(3H,s), 1.73(3~1,s), 2.05 to 2.55(3~1,m), 2.99(1H,m), 3.20 to 3.45(3H,m), 3.35(3H,s), 4.22(1H,m), 5.19(lH,m), 7.10 to 7.45(5~1,m).
[~]26_4l 4 (c 0.21, CHC~3) Elemental analysis for C22H32O4S :
Calcd. C:67.31~, H:8.22~, Found C:67.36%, H:8.30%.
Example 22 4~0-(Chloroacety].carbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-phenylthiomethyl-1,4-cyclohexanediol LiXewise in Example 12, from 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-l-phenylthiomethyl-l~4 cyclohexanediol (450 mg) was obtained 4-O-(chloro-acetylcarbamoyl)-2~ 2-epoxy-l r 5-dimethyl-4-hexenyl)-3-methoxy-1-phenylthiomethyl-1,4-cyclohexanediol (541 mg: yield 92%) as colorless powder.
NMR spectrum (~ value; CDCQ3): 1.46(3H,s), 1.66(3H,s), 1.73(3X,s), 1.50 to 1.92(4H,m~, 2.00 to 2.55(3H,m), 2.96(1H,t,6Hz), 3.23(3H,s), 3.38(2H,s), 3.25 to 3.50(1H,m), 4.52(2H,s), 5.18(1H,m), 5.45(1H,m), 7.15 to 7.45(5H,m).
[~]26-56.0 (c 0.21, CHCQ3).
Elemental analysis for Cz5H34NO6SCl:
Calcd. C:58.64%, H: 6.69%, N:2.74%, Found C:58.41%, H:6.69%, N:2.79%
Example 23 4-O-(Chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-phenylsulfinylmethyl-1,4-cyclohexanediol - 67 - 2n~
In dlchloromethane (2 ml) was dissolved 4 O-(chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-h-exenyl)-3-methoxy-1-phenylthiomethyl-1,4-cyclohexanediol (200 m~). To t:he solution was added, under ice-cooling, m-chloroperbenzoic acid (80.9 mg), and the mixture was stirred for 30 minutes. The reaction mixture was diluted with ethyl acetate ~70 ml), which was washed with a saturated aqueous solution o~ sodium hydrogencarbonate and a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was then purified by means of a silica gel column chromatography (carrier 10 g, developing solvent: ethyl acetate - hexane = 1:2) to afford 4-O-(chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-phenylsulfinylmethyl-l,4-cyclohexanediol (175 mg: yield 85%) as colorless powder.
NMR spectrum (~ value; CDC~3): 1.49(3H,s), 1.65(3H,s), 1.73(3H,s), 1.55 to 2.55(7H,m), 2.98(1H,t,6Hz), 3.31(1H,d,14Hz), 3.25 to 3.45(5H,m), 4.47(2H,s), 5.05 to 5.2S(lH,m), 5.49(1H,m), 7.50 to 7.70(5H,m)-[~]D6-88.6 (c 0.22, CHC~3).
Elemental analysis for C25H34NO7SC~Ø5H2O:
Calcd. C:55.91%, H:6.57%, N:2.61%, Found C:55.18%, H:6.39%, N:2.68%.
Example 24 4-O-(chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-iodomethyl-1,4-cyclohexanediol Likewise in Example 12, from 2-(1,2-epoxy-lr5 dimethyl-4-hexenyl)-3-methoxy-1-iodomethyl-1,4-cyclohexanediol (200 mg) was obtained 4-O-(N-chloro-acetylcarbamoyl)-2-(1,2~epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-iodomethyl-1,4-cyclohexanediol (222 mg:
- 68 - 2~
yield 86%) as colorless crystals, m.p. 140 to 141C.
NMR spectrum (~ value; CDC~3): 1.45 to 2.00(4~,m), 1.53(3H,s), 1.67(4H,s), 1.75(3H,s), 2.10 to 2.55(3H,m), 3.30(1H,m), 3.32(3H,s), 3.51(1H,d,lO~Iz), 3.53(1H,d,lOHz), 4.51(2H,s), 5.18(1H,m), 5~44(lH,m).
[a]D6~74.5 (c 0.22, CHC~3).
Elemental analysis for Cl9H29NO6ClI:
Calcd. C:43.07~, H:5.52%, Ns2.64%, Found C:42.81%, H:5.45%, N:2.65%.
Example 25 4-O-Acetyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-iodomethyl-3-methoxy-1,4-cyclohexanediol In dichloromethane (5 ml) was dissolved 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-iodomethyl-1,4-cyclohexanediol (2.08 g). To the solution were added dimethylaminopyridine (0.74 g) and acetic anhydride (0.58 ml)~ The mixture was stirred for 30 minutes. The reaction mixture was diluted with ethyl acetate (50 ml), which was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, then the solvent was purified by means of a silica gel column chromatography (carrier lO0 g, developing solvent:
ethyl acetate - hexane = 1:3) to afford 4-O-acetyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-iodomethyl-3-methoxy-1,4-cyclohexanediol (2.19 g: yield 95%) as a colorless oily product.
NMR spectrum (~ value; CDCR3): 1.52(3H,s), 1.53(1H,m), 1.66(3H,s), 1.74(3H,s), 1.65 to 2.00(4H,m), 2.12(3H,s), 2.10 to 2.60(3H,m), 2.98(1H,t,6Hz), 3.26(1H,m), 3.55(2H,s), 5.18(1H,m), 5.44(1H,m).
[a]26-66.5 (c 0.20, CHC~3).
~ 69 - 2 Example 26 4-(N'-Chloroacetylureido)-2-(1,2-epoxy-1,5-dimethyl-4-he~enyl)-3-methoxy-l-methylthiomethyl-1-cyclohexanol In methanol (5 ml) were dissolved 2-(1,2-epoxy-1,5-dimethyl-~-hexenyl)-3 methoxy-1-methylthiomethyl-4-oxy-l-cyclohexanol (200 mg) and ammonium acetate (487 mg). To the solution was added sodium cyanoborohydride (40 mg), and the mixture was stiLred ~or one hour. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate (50 ml).
The solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in dichloromethane (2 ml). To the solution was added dropwise at 0C
chloroacetylisocyanate (0.08 ml). The mixture was stirred for 15 minutes at the same temperature, which was then diluted with ethyl acetate (50 ml). The solution was washed with a saturated aqueous solution o~ sodium hydrogencarbonate and a saturated a~ueous solution of sodium chloride, followed by drying over anhydrous magnesium sulfate. The solvent was distilled of under reduced pressure, and the residue was purified by means of a silica gel column chromatography (carrier 25 g, developing solvent: ethyl acetate hexane = 1:3) to afford 4-(N~-chloroacetylureido)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-l-cyclohexanol (129 mg: yield 45%) as colorless powder.
NMR spectrum (~ ~alue; CDC~3): 1.48(3H,s), 1.40 to 2.55(7H,m), 1.66(3H,s), 1.73(3H,s), 2.20(3H,s), 2.85(1H,d,13Hz), 2.g9(1H,t,6Hz), 2.96(1H,d,13Hz), 3.32(3H,s), 3.40(1H,dd,4Hz,12Hz), 4.14(2H,s), 4.51(lH,m), 5.18(lH,m).
~ 70 - 2~ 3 ~i~
[~]D 60.8 (c 0.21,CHC~3).
Elemental analysis for C20H33N2O5C1Ø2H2O:
Calcd. C:53.07~, H:7.44%, N:6.19~, Found C:52.81%, H:7.42~, N:6.57~.
s Example 27 4 (N'-chloroacetylureido)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-dimethylsulfoniomethyl-1-cyclohexanol iodide Likewise in Example 13, from 4-(N'-chloro-acetylureido)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-l-methylthiomethyl-1-cyclohexanol (132 mg) was obtained 4-(N'-chloroacetylureido)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-]nethoxy-1-dimethylsulfoniomethyl-1-cyclohexanol. iodide (130 mg: yield 100%) as a pale yellow powdexy product.
NMR spectrum (~ value, CD30D): 1.40 to2.55(7H,m), 1-47(3H~s)~ 1-69(3H,s), 1.75t3H,s), 2.97(3H,s), 3.04(3H,s), 3.14(1H,t,6Hz), 3.31(3H,s), 3.51(1H,m), 3.67(1H,d,13Hz), 3.83(2H,s), 4.03(1H,d,13Hz), 4.41(1H,m), 5.24(1H,m).
Elemental analysis for C2lH38N2O5SClI.4H2O:
Calcd. C:38~04%, N:4.23%, Found C:37.91%, N:4.41%.
Example 28 4-O-(~hloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylsulfinylmethyl-1,4-cyclohexanediol Likewise in Example 23, from 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (156 mg) was obtained 4-O-(chloro-acetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylsul~inylmethyl-1,4-cyclohexanediol (156 mg: yield 100%) as colorless powder.
NMR spectrum (~ ~alue; CDC~3): 1.45(1.5H,s), - 71 - 2~2~3~
1.50(1.5H,s), 1.67(3H,s), 1.74(3H,5), 1.70 to 2.60(7H,m), 2.68(1.5H,s), 2.72(1.5H,s), 2.95(1H,t,6Hz), 3 15 to 3.28(3H,m), 3.31(1.5H,s), 3.37(1.5H,s), 4.48(2H,s), 5.20(lH,m), 5.46(lH,m).
~ 26 _90 o (c 0.20,CHC~3)-Elemqntal analysis ~or C20H32NO7SCl-H2O:
Calcd. C:49.63~, H:7.0~, N:2.89~, Found C:49.49%, H:6.73%, N:2.89%.
Example 29 4-O-(Chloroacetylcarbamoyl)-2-(1,2-epoxy-1.5-di.methyl-4-hexenyl)-3-methoxy-1-methylsulfonylmethyl-1,~-cyclohexanediol 4-O~(chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexellyl)-3-methoxy-l-methylsulfinylmethy].-1,4-cyclohexanediol (300 mg) was dissolved in dichloromethane (2 ml), to which was added, under ice-cooling, m-chloroperbenzoic acid (179 mg), and the mixture was stirred for one hour. The reaction mixture was diluted with ethyl acetate (70 ml), which was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by a silica gel column chromatography (carrier 15 g, developing solvent: ethyl acetate - hexane 2:1) to afford 4-O-(chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-h exenyl)-3-methoxy-1-phenylsulfonylmethyl-1 r 4~ ~
cyclohexanediol (91 mg: yield 30%) as colorless powder.
NMR spectrum (~ value: CDCQ3): 1.47(3H,s), 1.67(3H,s), 1.75(3H,s), 1.70 to 2.60(7H,m), 3.00(1H,m) 3.05(3H,s), 3.25 to 3.45(2H,m), 3.33(3H,s), 3.80(1H,d,15Hz), 4.47(2H,s), 5.17(1H,m), 5.46(1H,m).
[~]D -96.5 (c 0.20, CHCQ3).
Elemental analysis for C20H32NO8~C1Ø7H2O:
- 72 - 2~
Calcd. C:48.57%, H:6.81%, N:2.83%, Found C:48.62%, H:6.57%, N:2.86%.
Example 30 2--(1,2-Epoxy-1,5-dimethyl-4-hexenyl)-3 methoxy-l-(4 pyridyl)thiomethyl-1,4-cyclohexanediol ~,ilcewise in Example 21, from ~uma~illol (1.00 g) was obtained 2-(1,2-epoxy-1,5-dimethyl)-4-hexenyl)-3-methoxy-1-(4-pyridyl)thiomethyl-1,4-cyclohexanediol (1.15 g: yield 81%) as a pale yellow oily product.
NMR spectrum (~ value; CDC~3): 1.47(3H,s), 1.50 to 1.90(4Hrm), 1.67(3H,s), 1.74(3H,s), 2.05 to 2.60(3H,m), 3.04(1H,t,6Hz), 3.2~(1H,d,13Hz), 3,29(1H,m), 3.35(3H,s), 3.50(1H,d,13Hz), 4.23(1H,m), 5.20(1H,m), 7.19(2H,m), 8.38(2H,m).
Example 31 4-O-(Chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4~hexenyl)-1-(4-pyridyl)thiomethyl-3~me-thoxy-1,4-cyclohexanediol Likewise in Example 12, from 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-(4-pyridyl)thiomethyl-1,4-cyclohexanediol (911 mg) was obtained 4-O-(chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5 dimethyl-4-h-exenyl)-1-~4-pyridyl)thiomethyl-3-methoxy-1,4-cyclohexanediol (1.02 g: yield 83%) as colorless powder.
NMR spectrum (~ value; CDC~3): 1.46(3H,s), 1.55 to 2.00(4H,m), 1.66(3H,s), 1.74(3H,s), 2.05 to 2.60(3H,m), 2.99(1H,t,6Hz), 3.25 to 3.40(2H,m), 3.33(3H,s), ; 3.50(1H,d,12Hz), 4.51(2H,s), 5.18(1H,m), 5.47(1H,m), 7.21(2H,m), 8.42(2H,m).
Elemental analysis for C24H33N2O6SC1Ø5H2O:
Calcd. C:55.22%, H:6.55%, N:5.37%, Found C:55.07%, H:6.19%, N:5.59%.
2 ~ 3 Example 32 4-O-(Chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-metho~y-1-(N-methyl-4-pyridinio)-thiomethyl-1,4-c~clohexanedi.ol iodide S Likewise in Example 13, ~rom 4-O-(chloroacetyl-carbamoyl) 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(4-pyridyl)thiomethyl-3-methoxy-1,4-cyclohexanediol (165 m~) was obtained 4-O-(chloroacetylcarbamoyl)-2~(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-(N-methyl-4-pyridinio)thiomethyl-1,4-cyclohexanediol iodide (212 mg: yield 100%) as pale yellow powder.
NMR spectrum (~ value; C~30D): 1.49(3H,s), 1.55 to 2.60(7H,m), 1.68(3H,s), 1.70(3H,s), 3.13(1H,m), 3.20 to 3.60(2H,m), 3.99(1H,m), 4.Q3(2H,s), 4-23(3H~s)~
5.25(3H,s), 5A47(1H,m), 7.99(2H,m), 8.52(2H,m).
Example 33 2-(1,2-Epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-l-(pyrimidin-2-yl)thiomethyl-1,4-cyclohexanediol Likewise in Example 21, ~rom ~umagillol (500 mg) was obtained 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-l-(pyrimidin-2-yl)thiomethyl-l~4-cyclohexanediol (426 mg: yield 61~) as an oily product.
NMR spectrum (~ value; CDC~3): 1.40 to 2.10(4H,m), 1.60(6H,s), 1.71(3H,s), 2.65(1H,d,14Hz)), 2.70 to 2.90(3H,m), 3.53(3H,s), 4.10 to 4.32(2H,m), 4.16(1H,d,15Hz), 5.23(1H,m), 6.92(1H,t,5Hz), 8.43(2H,d,SHz) Example 34 4-O-(Chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-(pyrimidin-2-yl)thiomethyl-1,4-cyclohexanediol Likewise in Example 12, ~rom 2-(1,2-epoxy-1,5-- 35 dimethyl-4-hexenyl)-1-(pyrimidin-2-yl)thiomethyl-3-methoxy-1,4-cyclohexanediol (300 mg) was obtained 4-O-2 ~ ,i ,,3 (chloroacetylcarbamo~1)-2-(1,2-epoxy-l,S-dimethyl-4-h-exenyl)-3-me~hoxy-1--(pyrimidin-2-yl)thiomethyl-1,4-cyclohexanediol (344 mg: yield 88%) as pale yellow powder.
NM~ spectrlm~ (~ value; CDCQ3): 1.57(3H,s), 1.5S to 2.05(4~1,m), 1.60(3H,s), 1.71(3~1,s), 2.67(1H,d,lS~Iz), 2.75 to 2.95(3H,m), 3.51(3H,m), 4.10(lH,d,15Hz), 4.26(1H,dd,lHz,llHz), 4.45(3H,s), 5.23(1H,m), 5.52(1H,m), 6.95(2H,t,SEIz), 8.49(1H,d,SHz).
Example 35 2-(1,2-Epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-ethylthiomethyl-1,4-cyclohexanediol Likewise in Example 21, from fumagillol (1.00 g), was obtained 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-l-ethylthiomethyl-1,4-cyclohexanediol (991 mg:
yield 81%) as a pale yellow product.
NMR spectrum (~ value; CDCQ3) 1.27(3H,t,7Hz), 1.46(3H,s), l.SO(lH,m), 1.67(3H,s), 1.74(3H,s), 1.60 to 1.90(3H,m), 2.05 to 2.5X(3H,m), 2.61(2H,q,7Hz), 2.80 to 3.00(3H,m), 3.35(3H,s), 4.22(1H,m), 5.20(1H,m).
Example 36 4-O-(Chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-ethylthiomethyl-1,4-cyclohexanediol Likewise in Example 12, from 2--(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-ethylthiomethyl-3-methoxy-1,4-cyclohexanediol (300 mg) was obtained 4-O-(chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5 dimethyl-4-h-exenyl)-3-methoxy-1-e~hylthiomethyl-1,4-cyclohexanediol (385 mg: yield 95%) as colorless powder.
NMR spectrum (~ value; CDCQ3): 1.29(3H,t,7Hz), 1.48(3H,s), 1.60(1H,m), 1.66(3H,s), 1.74(3H,s), 1.60 to 1.95(3H,m), 2.05 to 2.60(3H,m), 2.62(2H,q,7Hz), 2.84(1H,d,13Hz), 2.93(1H,m), 3.01(1H,d,13Hz), - 75 - ~ ~ L~
3.32(3H,s), 3.35(1H,m), 4.52(2H,s), 5.19(1H,m), .44(1H,m)-Example 37 2-(1,2-Epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-benzylthiomethyl-1,4-cyclohexanediol Likewise in Example 21, from ~umagillol (S00 mg) was obtained 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-benzylthiomethyl-1,4-cyclohexanediol (652 mg:
yield 90~) as a colorless oi:ly product.
NMR spectrum (~ value; CDC~3): 1.38(3H,s), 1.48(1H,m), 1.66(3H,s), 1.74(3H,s), 1.55 to 1.90(3H,m), 2.05 to 2.55(3H,m), 2.75 to 3.00(3H,m), 3.30(lH,m), 3.33(3H,s), 3.74(lH,d,12Hz), 3.80(1H,d,12Hz), 5.19(lH,m), 7.15 to 7.40(5H,m).
Elemental Analysis for C23H34O4SØ32O:
Calcd. C:67.05%, H:8.45%, Found C:67.03%, H:8.54~.
Example 38 4-O-(Chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-benzylthiomethyl~1,4-cyclohexanediol Likewise in Example 12, from 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-benzylthiomethyl-3-methoxy-1,4-cyclohexanediol (461 mg) was obtained 4-O-(chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-h-exenyl)-3-methoxy-1-benzylthiomethyl-1,4 cyclohexanediol (544 mg: yield 91%) as colorless powder.
NMR spectrum (~ value; CDC~3): 1.40t3H,s), 1.45 to 1.90(4H,m), 1.65(3H,s), 1.73(3H,s), 2.05 to 2.60(3H,m), 2.77(lH,d,13Hz), 2.88(lH,m), 2.93(lH,d,13Hz), 4.50(3H,s), 3.76(1H,d,13Hz), 3.80(1H,d,13Hz), 4.50(2H,s), 5.17(1H,m), 5.42(1H,m), 7.20 to 7.40(5H,m).
- 76 - 2~
Example 39 2-(1,2-Epoxy-1,5-dimethyl-~-hexenyl)-3-methoxy-1-allylthiomethyl-1,4-cyclohexanediol Likewise in Example 21, from fumagillol (500 mg) was obtained 2-(1,2-epoxy-l,S-dimethyl-4-hexenyl)-3-methoxy-1-allylthiomethyl-1,~-cyclohexanediol ~555 mg:
yield 88%) as a colorless oily product.
NMR spectrllm (~ value; CDC~3): 1.45(3H,s), 1.52(1H,m), 1.66(3H,s), 1.7~(3H,s), 1.60 to 1.95(3H,m), 2.05 to 2.55(3H,m), 2.83(2H,s), 2.95(1H,t,6Hz), 3.19(2H,d,7Hz), 3.30(1H,m), 3.34(3H,s), 4.22(1H,m), S.05 to 5.25(3H,m), 5.57 to 5.92(lH,m).
Elemental Analysis for ClgH~2O4S:
Calcd. C:64.01%, H:9.05%, Found C:63.71~, H:9.23%
Example 40 4-O-(Chloroacetylcarbamoyl)-2-(1,2-epoxy~1,5-dimethyl-4-hexenyl)-3-methoxy-1-allylthiomethyl-1,4-cyclohexanediol Likewise in Example 12, from 2-(1,2-epoxy-l,S-dimethyl-4-hexenyl)-l-allylthiomethyl-3-methoxy-1,4-cyclohexanediol (374 mg) was obtained 4-O-(chloroacetylcarbamoyl)-2-(1,2-epoxy-l,S-dimethyl-4-h-exenyl)-3-methoxy-1-allylthiomethyl-1,4-cyclohexanediol (441 mg: yield 88%) as colorless powder.
NMR spectrum (~ value; CDC~3): 1.47(3H,s), 1.55 to 1.95(4H,m), 1.66(3H,s), 1.74(3H,s), 2.05 to 2.55(3H,m), 2.80(lH,d,13Hz), 2.91(lH,d,13Hz), 2.92(lH,m), 3.20(3H,d,7Hz), 3.32(3H,s), 3.35(1H,m), 4.51(2H,s), S.lO to 5.25(3H,m), 5.44(lH,m), 5.72 to 7.93(lH,m).
Example 41 4-O-(N-Chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)~3-methoxy-1-allylmethyl-sulfoniomethyl-1,4-cyclohexanediol bromide _ 77 - ~2~13~6 Likewise in Example 13, from 4-O-(N-chloroacetyl-carbamo~l) 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-l-methylthiomethyl-1,4-cyclohexanediol (120 mg) was ohtained 4-O-(N-chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-allylmethyl-s~llfoniomethyl-1,4--cyclohexanediol bromide (126 mg:
yield 82~) as colorless powder.
NMR spectrum (~ value; CD30D): 1.35 to 1.50(6H,m), 1.69(3H,s), 1.75(3H,s), 1.60 to 2.60(7H,m), 2.90(1.5H,s), 3.02(1.5H,s), 2.95 to 3.70(6H,m), 4.18(2H,m), 4.44(lH,m), 5.15 to 6.15(5H,m).
Example 42 4-O-Phenoxycarbonyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthionmethyl-1,4-cyclohexanediol In dichloromethane (2 ml) were dissolved 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylth-iomethyl-1,4-cyclohexanediol (200 mg) and dimethylaminopyridine (115 mg). To the solution was added, under ice-cooling, phenyl chloroformate (95 ~1), and the mixture was stirred for 16 hours. The reaction mixture was diluted with ethyl acetate (70 ml), washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (carrier 10 g, developing solvent: ethyl acetate - hexane = 1:4) to afford 4-O-phenoxycarbonyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (222mg: yield 81%) as a colorless oily product.
NMR spectrum (~ value, CDC~3): 1.48(3H,s~, 1.67(3H,s), 1.74(3H,s), 1.65 to a.95(4H,m), 2.10 to - 78 ~ 2~
2.55(3H,m), 2.2)(3H,s), 2.87(1H,d,13Hz), 2 95(1H,t,7Hz), 2.96(1H,d,13Hz), 3.35(3H,s), 3.35(1H,m), 5.20(1H,m~, 5.39(1H,m), 7.15 to 7.45(5H,m).
Example 43 4-O-Phenoxycarbonyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-dimetllylsuloniomethyl-1,4-cyclohexanediol iodide Likew.ise in Example 13, from 4-O-phenoxycarbonyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-c~clohexanediol tl45 mg) was obtained 4-O-phenoxycarbonyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-dimethylsulfoniomethyl-1,4-cyclohexanediol iodide (165 mg: yield 87~) as pale yellow powder.
NMR spectrum (~ value; CD30D): 1.49(3H,s), 1.69(3H,s), 1.76(3H,s), ]..65 to 2.05(4H,m), 2.10 to 2-60(3H~m), 3.01(3H,5), 2.99(3H,s), 3.07(3H,s), 3.13(1H,t,6Hz), 3.38(3H,s), 3.52(1H,dd,3Hz,12Hz), 3.67(1H,d,14Hz), 4.04(1H,14Hz), 4.86(2H,s), 5.26(1H,m), 7.12 to 7.~7(5H,m).
Example 44 4-O-Benzoyl-2-(1,2-epoxy~1,5-dim~thyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol Likewise in Example 42, from 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3~methoxy-l-methylthiomethyl-1,4-cyclohexanediol (100 mg) was obtained 4-O-benzoyl 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (91 mg: yield 69%) as a colorless oily product.
NMR spectrum (~ value; CDC~3): 1.50(3H,s), 1.66(3H,s), 1.73(3H,s), 1.60 to 2.60(7H,m), 2.24(3H,s), 2.85(1H,d,13Hz), 3.00(1H,t,6Hz), 3.09(1H,d,13Hz), 3.33(3H,s), 3.40(1H,m), 5.19(1H,m), 5.74(1H,m), 7.40 to 7.65(3H,m), 8.08(2H,m).
- 79 - ~ ~2'~3 Example 45 4-O-Tosyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-l-methylthiomethyl-1,4-cyclohexanediol Likewise in Example 42, from 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-:l-methylthiomethyl-1,4-cyclohexanediol t200 mg) was obtained 4~0-tosyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl) 3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (57 mg: yield 19%) as a colorless oily product.
NMR spectrum (~ value; CDC~3): 1.40(3H,s), 1.64(3H,s), 1.72(3H,s), 1.60 to 1.95(4H,m), 2.05 to 2.50(3H,m), 2.13(3H,s), 2.45(3H,m), 2.85(1H,d,13Hz), 2.86(1H,t,6Hz), 2.93(1H,d,13Hz), 3.06(3H,s), 3.20(lH,m), 5.02(lH,m), 5.16(lH,m), 7.34(2H,d,8Hz), 7.84(2H,d,8Hz).
Example 46 4-O-Mesyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-iodomethyl-1,4-cyclohexanediol Likewise Example 42, from 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-iodomethyl-1,4-cyclohexanediol (300 mg) was obtained 4-O-mesyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-iodomethyl-1,4-cyclohexanediol (314 mg: yield 88%) as a calorless oily product.
NMR spectrum t~ value; CDC~3): 1.51(3H,s), 1.60(1H,m), 1.66(3H,s), 1.74(3H,s), 1.80 to 2.55(6H,m), 2.95(1H,t,6Hz), 3.11(3Hrs), 3.30(1H,m), 3.38(3H,s), 3.53(lH,d,llHz), 3.56(lH,d,llHz), 5.19(lH,m), 5.22(lH,m).
Example 47 4-O-Mesyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol Li~ewise in Example 10, from 4-O-mesyl-2~(1,2-3 ~3 ~
epoxy-1,5~dimethyl-4~hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (179 mg) was obtained 4-O-mesyl-2-(1,2-epoxy-1,5-dimethyl-4-hexen~l)-3--methoxy-1-methylthiomethyl-1,4-S cyclohexanediol (112 mg: yield 74~) as a colorless oilyproduct.
NM~ spectrum (S value; CDC~): 1.46(3H,s), 1.67(3H,s), 1.74(3H,s), 1.65 to 2.55(7EI,m), 2.20(3H,s), 2.91(3H,m), 3.11(3H,s), 3.34(1H,m), 3.38(3H,s), 5.19(lH,m), 5.24(lH,m).
Example 48 2-(1,2-Epo~y-l,S-dimethyl-4-hexenyl)-3-methoxy-1-(pyrrolidin-1-yl)methyl-1,4-cyclohexanediol N-oxide lS Fumagillol (S00 mg) was dissolved in pyrrolidine (1 ml), and the solution was stirred at 50C overnight.
Excess volume of pyrrolidine was distilled off under reduced pressure to leave 2-(1,2-epoxy-l,S-dimethyl-4-hexenyl)-3-methoxy-1-(pyrrolidi~ yl)methyl-1,4-cyclohexanediol as a crude product. This crude product was dissolved in chloroform (5 ml), to which was added m-chloroperbenzoic acid (458 mg), and the mi.xture was stirred for 30 minutes. The solvent was distilled of~
under reduced pressure, and the residue was purified by means of a silica gel column chromatography (carrier 25 g, developing solvent: chloroform - methanol -am~oniacal water = 15:1:0.1) to obtain 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-(pyrrolidin-1-yl)methyl-1,4-cyclohexanediol N-oxide (554 mg: yield 84%) as colorless powder.
NMR spectrum (~ value; CDC~3): 1.43(1H,d,9Hz), 1.51(3H,s), 1.68(3H,s), 1.71(3H,s), 1.65 to 2.65(6H,m), 2.95(1H,d,13Hz), 3.15 to 3.55(4H,m), 3.48(3H,s), 3.88(3H,m), 4.28(lH,m), 5.24(lH,m).
[~]D6-20.so (c 0.21,CHCQ3).
Elemental Analysis for C20H35NO5.H2O:
- 81 - 2~2~3~,~
Calcd. C:61.99%, H:9.62%, N:3.61%, Found C:62.02%, H:9.60~, N:3.60%.
Example 49 S 4-O-Chloroacetylcarbamoyl~2-(1,2-epoxy-1,5-dimethyl-4-hexellyl)-3-methoxy-1-(pyrrolidin-1-yl)methyl-1,4-cyclohexanediol N-oxide Likew.ise in Exampl.e 12, from 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methox~-1-(pyrrolidin-1-yl)methyl-1,4-cyclohexanediol N-oxide (350 mg) was obtained 4-O-chloroacetylcarbamoyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-pyrrolidin-1-yl)methyl-1,4-cyclohexanediol N-oxide (74 mg: yield 16%) as colorless powder.
NMR spectrum (~ value; CDC~3): 1.47t3H,s), 1.20 to 2.80(11H,m), 1.68(3H,s), 1.72(3H,s), 3.20 to 4.10(7H,m), 3.42(3H,s), 4.49(2H,s), 5.22(1H,m), 5.48(lH,m).
~]26_4l o (c 0.20, CHC~3)-Elemental Analysis for C23H37O7Cl.H2O:
Calcd. C:54.49%, H:7.75%, Found C:54.17%, ~:7.33%.
Example 50 2-(1,2-Epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-(N-methylpyrrolidin-l-ylio)methyl-1,4-cyclohexanediol iodide Fumagillol (500 mg) was dissolved in pyrrolidine (1 ml), and the solution was stirred at 50C overnight.
Excess volume of pyrrolidine was distilled off under reduced pressure to leave 2~(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-(pyrrolidin-1-yl~methyl-1,4-cyclohexanediol as a crude product. This crude product was dissolved in dichloromethane (5 ml), to which was added methyl iodide (1.1 ml), and the mixture W2S
stirred overnight. The solvent was distilled off under - 82 ~
reduced pressure, and the residue was puri~ied by means of a silica gel column chromatography ~developing solvent: chloroform-methanol-ammoniacal water =
10:1:0.1), followed by pulverizincJ with ether to obtain 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy~ N-methylpyrrolidin-l-ylio)methyl-1,4-cyclohexanediol iodide (446 mg: yield 50~) as colorless powder.
NMR spectrum (~ value; CD30D): 1.45(3H,s), 1.68(3H,s), 1.75(3H,s), 1.65 to 2.60(11H,m), 3.05 to 3.45(2H,m), 3.23(3H,s), 3.34(3H,s), 3.55 to 3.90(4H,m), 3.62(1H,d,14Hz), 3.92(1H,d,14Hz), 4.25(1H,m), 5.25(lH,m).
Example 51 4-O-Chloroacetylcarbamoyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-(N-methylpyrrolidin-l-ylio)methyl-1,4-cyclohexanediol iodide Likewise in Example 12, from 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-(N-methylpyrrolidin-1-ylio)methyl-1,4-cyclohexanediol iodide (200 mg), was obtained 4-O-chloroacetylcarbamoyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-(N-methylpyrrolidin-l-ylio)methyl-1,4-cyclohexanediol iodide (76 mg: yield 30%) as colorless powder.
NMR spectrum (~ value; CD30D): 1.46(3H,s), 1.68(3H,s), 1.-75(3H,s), 1.80 to 2.60(11H,m), 3.14(1H,t,6Hz), 3.25(3H,s), 3.34(3H,s), 3.46(1H,m), 3.60 to 3.90(4H,m), 3.69(1H,d,14Hz)`, 3.95(1H,d,14Hz), 3.46(2H,s), 5.24(1H,m), 5.46(1H,m).
3~
Example 52 4~-(Morpholino)carbonyloxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl cyclohexanol Likewise in Example 10, from 4~-(morpholino)- ~
carbonyloxy~6-epifumagillol (110 mg) was obtained 4~-O-(morpholino)carbonyl-2-(1,2-epoxy-1,5-dimethyl-4-hexen-- g3 ~
yl)-3-methoxy-1-methylthiomethylcyclohexanol (81 mg:
yield 64%) as a colorless oily product.
NMR spectrum (~ value; CDC~3): 1.47(3H,s), 1.66t3H,s), 1.74(3H,s), 1.50 to 2.45(7H,m), 2.83(1H,d,13Hz), 2.94(1H,d,13Hæ), 3.05(1~,t,6Hz), 3.35 to 3.80(~H,m), 4.69(1~l,m), 5.~2(lM,m).
Example 53 4~-Hexylamino-2~(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-l~methylthiomethylcyclohexanol Likewise in Example lO, fxom 6~-hexylamino~6-desoxyfumagillol (110 mg) was obtained 4~ hexylamino-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethylcyclohexanol (110 mg: yield 88%) as a colorless oily product.
NMR spectrum (~ value; CDCR3): 0.88(3H,m), 1.20 to 1.90(12H,m), 1.48(3H,s), 1.65(3H,s), 1.73(3H,s), 2.17(3H,s), 2.32(2H,m), 2.50(2H,m), 2.71(lH,m), 2.78(1H,d,13Hz), 2.91(1H,d,13Hz), 3.03(1H,m), 3.40(2H,m), 3.48(3H,s), 5.23(lH,m).
Example 54 l-(~-Bromobenzyl)methylsulfoniomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol bromide In chloroform (0.5 ml) were dissolved 2-(1,2-epoxy-1,5-dimethyl-4-hexenylj-3-methoxy-l-methylth-iomethyl-1,4-cyclohexanediol (200 mg) and 4-bromobenzyl bromide (756 mg). To the solution was added silver bromide (11.4 mg), and the mixture was stirred for 28 hours. Insolubles were filtered off, and the solvent was distilled off. The residue was pulverized by~the addition of ether. The resul~ing powder was dissolved in methanol (2 ml). Insolubles were fil~ered off, then the solvent was distilled off under reduced pressure.
The residue was pulverized by the addition of ether to ~ ~ ~ L~ 3 ~ ~
give 1-(4-bromobenzyl)methylsulfoniomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol bromide (176 mg: yield 50%) as colorless powder.
NMR spectrum (~ value; CD30D): 1.43(3H,s), 1.68(3H,s), 1.55 to 1.90(4H,m), ~.10 to 2.55(3H,m), 2.~2(1.5,s), 3.10(1H,t,6}~z), 3.27(1H,m), 3.33(1.5H,s), 3.35(1.5H,s), 3.54(1H,m), 3.86 to 4.12(1H,m), 4.24(lH,m), 4.50 to 4.92(2H,m), 5.24(lH,m), 7.48(2H,m), 7.69(2H,m).
Example 55 1-(4-Chlorobenzyl)methylsulfoniomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol bromide Likewise in Example 54, 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (200 mg) wa~ allowed to react with 4-chlorobenzyl bromide (1.24 g) to yive 1-(4-chlorobenzyl)methylsulfoniometh~1-2~(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol bromide (228 mg: yield 70~) as colorless powder.
NMR spectrum (~ value; CD30D): 1.43(3H,s), 1.68(3H,s), 1.75(3H,s), 1.55 to 1.90(4H,m), 2.10 to 2.55(3H,m), 2.82(1.5H,s), 2.99(1.5H,s), 3.09(1Htt,6Hz), 3.27(1H,m), 3.33(1.5H,s), 3.35(1.5H,s), 3.54(1H,m), 3.88 to 4.11(1H,m), 4.24(1H,m), 4.50(0.5H,d,18~z), 4.71(1H,s), 4.91(0.5H,d,18Hz), 5.23(1H,m), 7.53(3H,m).
Example 56 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(4-fluorobenzyl)methylsulfoniomethyl-3-methoxy-1,4-cyclohexanediol bromide Likewise in Example 54, 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclo-hexanediol (200 mg) was allowed to react with 4-r~
fluorobenzyl bromide (1.14 g) to give 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(4-fluorobenzyl)methyl-sulfoniomethyl-3-methoxy-1,4-cyclohexanediol bromide t223 mg: yield 71%) as colorless powder.
NMR spectrum (~ value; CD30D): 1.'~3(3H,s), 1.68(3H,s), 1.7~(3H,s), 1.55 to 1.90(4H,m), 2.10 to 2.55(3H,m), 2.80(1.5}l,s), 2.98(1.5H,s), 3.10(1H,t,6Hz), 3.25(1H,m), 3.33(1.5H,s), 3.35(1.5H,s), 3.53(1H,m), 3.85 to 4.12(1H,m), 4.24(1H,m), 4.60(0.5H,d,17Hz), 4.71(lH,s), 4.92(0.5H,d,17Hz), 5.23(lH,m), 7.25(2H,m), 7.59(2H,m).
Example 57 2-(1,2-Epoxy-1,5-dimethyl-4--hexenyl)-3-methoxy-1-(4-methylbenzyl)methylsulfoniomethyl-1,4-cyclohexanediol bromide Likewise in Example 54, 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclo-hexanediol (200 mg) was ~llowed to react with 4-methylbenzyl bromide (1.12 g) to give 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)~3-methoxy-1-(4-methylbenzyl)-methylsulfoniomethyl-1,4-cyclohexanediol bromide (198 mg: yield 56~) as colorless powder.
NMR spectrum (~ value; CD30D): 1.42(1,5H,s), 1.44(1.5H,s),1.68(3H,s), 1.74(3H,s), 1.55 to 1.90(4H,m), 2.39(3H,s), 2.10 to 2.55(3H,m), ; 2.75(1.5H,s), 2.94(1.5H,s), 3.08(1H,t,6Hz), 3.27(1H,m), 3.33(1.5H,s), 3.35(1.5H,s), 3.49(1H,d,12Hz), 3.80 to 4.10(1H,m), 4.24(1H,m), 4.61(0.5H,d,13Hz), 4.66(1H,s), 4.87(0.5H,d,13Hz), 5.23(lH,m), 7.37(4H,m).
Example 58 1-(3-Bromobenzyl)methylsulfoniomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol bromide Likewise in Example 54, 2-(1,2-epoxy-1,5-dimethyl-2 ~ 7, ~
4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclo-hexanediol (200 mg) was allowed to react with 3-bromobenzyl bromide (1.51 g) to ~ive 1-(3-bromobenzyl)-methylsulfoniomethyl-2-(l,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol bromide (184 m~:
yield 52%) as colorless powder.
NMR spectrum (~ value; CD30D): 1.44(3H,s), 1.68(3H,s), 1.7~t3H,s), 1.55 to 1.90(4H,m), 2.10 to 2.55(3H,m), 2.83(1.5H,s), 3.10(1H,t,6Hz), 3.25(1H,m), 3.33(1.5H,s), 3.35(1.5H,s), 3.53(1H,m), 3.8S to 4.12(1H,m), 4.24(1H,m), 4.60(0.5H,d,17Hz), 4.69(1H,s), 4.83(0.5H,d,17Hz), 5.23(1H,m), 7.35 to 7.85(4H,m).
Example 59 1-(2-Bromobenzyl)methylsulfoniomethyl-2-(1,2-epoxy-1,5-d.imethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol bromide Likewise in Example 54, 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclo-hexanediol (200 mg) was allowed to react with 2-bromobenzyl bromi~e (1.51 g) to give 1-(2-bromobenzyl)-methylsulfoniomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol bromide (29 mg:
yield 8%) as colorless powder.
NMR spectrum (~ value; CD30D): 1.46(3H,s), 1.69(3H,s), 1.75(3H,s), 1.55 to 1.95(4H,m), 2.10 to 2.55(3H,m), 2.90(1.5H,s), 3.08(1.5H,s), 3.11(1H,t,6Hz), 3.25(1H,m), 3.31(1.5H,s), 3.35(1.5H,s), 3.63 to 4.05(2H,m), 4.24(1H,m), 4.66(1H,~), 4.78(0.5H,d,13Hz), 5.18(0.5H,d,13Hz), 5.23(lH,m), 7.15 to 7.83(4H,m).
Example 60 1-(4-Bromobenzyl)methylsulfoniomethyl-4-(N-chloroacetylcarbamoyloxy)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol bromide To a solution of 1-(2-bromobenzyl)methyl-2 ~
sulfoniomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol bromide (150 mg) in dichloromethane (2 ml) was added dropwise, under ice-cooling, chloroacetylisoc~anate (40 ml), then the mixture was stirred ~or 30 minutes. To the reaction mixture was added water ~o suspend the reaction. The product was ex~racted with ethyl acetate. The or~anic layer was washed with a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (carrier 10 g, developing solvent : chloroform-methanol=20:1) to give 1-(4-bromobenzyl)methylsulfoniomethyl-4-(N-lS chloroacetylcarbamoyloxy)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol bromide (80 mg: yield 44%).
NMR spectrum (~ value; CD30D): 1.43(3H,s), 1.68(3H,s), 1.74(3H,s), 1.50 to 2.00(4H,m), 2.10 to 2.55(3H,m), 2.86(1.5H,s), 3.01(1.5H,s), 3.10(1~,t,6Hz), 3.34(1.5H,s), 3.37(1.5H,s), 3.45(1H,m), 3.57(1H,m), 3.gO to 4.15(1H,m), 4.43(2H,s), 4.60(0.5H,d,13Hz), 4.73(1H,s), 4.91(0.5H,d,13Hz), 5.23(1H,m), 5.45(1H,m), 7.49(2H,m), 7.69(2H,m).
[~]D5-43.50 (c 0.20, CHCQ3).
Example 61 4-(N-Chloroacetylcarbamoyloxy)-1-(4-chlorobenzyl)methylsulfoniomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)~3-methoxycyclohexanol bromide Likewise in Example 60, from 1-(4-chlorobenzyl)-methylsulfoniomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol (183 mg) was obtained 4-(N-chloroacetylcarbamoyloxy)-1~(4-chlorobenzyl)methylsulfoniomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol bromide (123 ~ ~ 2 ~
- ~8 -mg: yield 55%) as colorless powder.
NMR spectrum (~ value; CD30D): 1.43(3H,s), 1.68(3H,s), 1.74(3H,s), 1.60 to 1.95(4H,m), 2.10 to 2.55(3H,m), 2.85(1.5H,s), 3.01(1.5H,s), 3.09(1~1,t,6Hz), 3.33(1.5H,s), 3.34(1.5H,s), 3.45(1H,m), 3.58~1H,m), 3 90 to 4.18(lH,m), ~.43(lH,m), ~.44(1H,s), 4.66 to 4.98(2H,m), 5.23(lH,m), 5.46(lH,m), 7.55(4H,m).
[a]D4-~5.2 (c 0.22, CHC~3).
Example 62 4-(N-Chloroacetylcarbamoyloxy)-2-(1,2-epoxy-1,5- , dimethyl-4-hexenyl)-1-(4-fluorobenzyl)-methylsulfoniomethyl-3-methoxycyclohexanol bromide Likewise in Example 60, from 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(4-fluorobenzyl)methyl~
sulfoniomethyl-3-methoxy-1,4-cyclohexanediol (181 mg) was obtained 4-(N-chloroacetylcarbamoyloxy)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl-1-(4-fluorobenzyl)-methylsulfoniomethyl-3-methoxycyclohexanol bromide (118 m~: yield 52%) as colorless powder.
NMR spectrum (~ value; CD30D): 1.43(3H,s), 1.68(3H,s), 1.74(3H,s), 1.50 to 1.95(4H,m), 2.10 to 2.55(3H,ml, 2.84(1.5H,s), 3.00(1.5H,s), 3.10(1H,t,6Hz), 3.33(1.5H,s), 3.35(1.5H,s), 3.45(1.5H,m), 3.58(1H,m), 3.90 to 4.18(lH,m), 4.43(lH,m), 4.44~lH,s), 4.70(0.5H,d,13Hz?, 4.87(1H,s), 4.99(0.5H,d,13Hz), 5.23(lH,m), 5.46(lH,m), 7.26(2H,m), 7.61(2H,m).
[a]24-53.3 (c 0.22, CHC~3).
Example 63 4-(N-Chloroacetylcarbamoyloxy)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl_-3-methoxy-1-(4-methylbenzyl)methylsulfoniomethylcyclohexanol bromide Likewise in Example 60, from 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-(4-methylbenzyl) methylsulfoniomethyl-1,4-cyclohexanediol (165 mg) was 3 ~ ~
obtained 4-(N-chloroacetylcarbamoyloxy)-2-(1,2-epoxy-1,S-dimethyl-4-hexenyl)-3-methoxy-1-(4-methylbenzyl)methylsulEoniomethylcyclohexanol bromide (107 mg: yield 52%) as colorless powder.
NMR spectrum (~ value; CD~OD): 1.42(1.5H,s), 1.~3(1.5H,s), 1.68(3H,s), 1.74(3H,s), l.SO to 1.95(4H,m), 2.39(3H,s), 2.10 to 2.55t3H,m), 2.79(1.5H,s~, 2.97(1.5H,s), 3.09(1H,t,6Hz), 3.32(1.5H,s), 3.35(1.5H,s), 3.45(1H,m),3.52(1H,m), 3.85 to 4.15(1H,m), 4.43(1H,m), 4.44(1H,s), 4.63(0.5H,d,13Hz), 4.69(1H,s), 4.92(0.5H,d,13Hz), 5.22(lH,m), 5.46(1H,m), 7.33(3H,m), 7.43(2H,m).
~]D4-46.40 (c 0.22, CHC~3).
lS Example 64 1-(3-Bromobenzyl)methylsulfoniomethyl-4-(N-chloroacetylcarbamoyloxy)-2-(1,2-epoxy-l,S-dimethyl-4-hexenyl)-3-methox~cyclohexanol bromide Likewise in Example 60, from 2-~1,2-epoxy-1,5-dimethyl 4-hexenyl)-3-methoxy-1-(4-methylbenzyl)-methylsulfoniomethyl-1,4-cyclohexanediol (222 mg) was obtained 1-(3-bromobenzyl)methylsulfoniomethyl-4-(N-chloroacetylcarbamoyloxy)-2-(l~2-epoxy-l~5-dimethyl-4 hexenyl)-3-methoxycyclohexanol bromide (171 mg: yield 64%) as colorless powder.
NMR spectrum (~ value; CD30D): 1.43(3H,s), 1.68(3H,s), 1.73(3H,s), 1.50 to 1.95(4H,m), 2.10 to 2.60(3H,m), 2.87(1.5H,s), 3.01(1.5H,s), 3.11(1H,t,6Hz), 3.32(1.5H~s), 3~34(1.5H,s), 3.45(1H,m), 3.57(1~,m), 3.90 to 4.15(1H,m), 4.64(0.5H,d,lOHz), 4.73(1H,s), 4.92(0.5H,d,lOHz), 5.22(1H,m), 5.46(1~,m), 7.35 to 7 90(4H,m)-[a]D2-38.3 (c 0.20, CHC~3).
Example 65 Separation of stereoisomers of 1-(3-bromobenzyl)methyl-go 2~2~
sulfoniomethyl~4-(N-chloroacetylcarbamoyloxy)-2-(1,2-epoxy-1 r 5-dimethyl-4-hexenyl)-3-methoxycyclohexanol bromide By sub-Jecting 1-(3-bromobenzyl)methylsulfonio-S methyl-4-(N-chloroacetylcarbamOylOxy) 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol bromide (150 my) obtainecl in substantially the same manner as Example 64 to a silica gel column chromatography (carr.ier 10 g, developing solvent: dichloromethane-methanol-water=20:1:0.2), a steroisomer showin~
relatively high Rf value in TLC (developing solvent:
chloroform-methanol=20:1) (isomer ~ : 60 mg) was success~ully separated from a stereoisomer showing relatively low RF value in the same T~C (isomer B : 62 mg), the respective isomers being as colorless powder.
Isomer A :
NMR spectrum (~ value; CD30D): 1.43(3H,s), 1.67(3H,s), 1.73(3H,s), 1.50 to 1.95(4H,m), 2.10 to 2.55(3H,m), 3.01(3H,s), 3.11(1H,m), 3.32(3H,s), 3.43(1H,m), 3.54(1H,d,13Hz), 3.98(1H,d,13Hz), 4.42(2H,s), 4.72(2H,s), 5.21(1H,m), 5.44(1H,m), 7.40 to 7.89(4H,m).
Isomer B :
NMR spectrum (S ~alue; CD30D): 1.43(3H,s), 1.68(3H,s), 1.74(3H,s), 1.50 to 1.95(4H,m), 2.10 to 2.60(3H,m), 2.86(3H,s), 3.11(1H,m), 3.34(3H,s), 3.43(1H,m), 3.53(1H,d,14Hz), 4.12(1H,d,14Hz), 4.43(2H,s~, 4.69(1H,d,13Hz), 4.73(1H,d,21Hz), 4.91(1H,d,13Hz), 5.01(1H,d,21Hz), 5.22(1H,m), 5.47(lH,m), 7.40 to 7.90(4H,m).
Example 66 1-Diallylsulfoniomethyl-2-(1,2 epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol perchlorate To a mixture of 1-allylthiomethyl-2-(1,2-epoxy-1,S-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol - gl -(300 m~) and allyl bromide (0.73 ml) was added silver perchlorate (192 mg) under ice-cooling, which was stirred for 30 minutes at room temperature. Insolubles were filtered off, and the solvent was distilled off S under reduced pressure. The residue was purified by means of a sillca gel column chromatography (carrier 30 g, developing solvent : chloroform-methanol=20:1) to give l-diallylsulfoniomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol perchlorate (160 mg: yield 37~) as colorless powder.
NMR spectrum (~ value; CD30D): 1.45(3H,s), 1.68(3H,s), 1.75(3H,s), 1.60 to 2.60(7H,m), 3.11(1H,t,6Hz), 3.29(1H,m), 3.34(3H,s), 3.90 to 4.35(7H,m), 5.25(lH,m), 5.55 to 6.15(6H,m).
Example 67 l-Diallylsulfoniomethyl-4-(N-chloroacetylcarbamoyloxy)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-cyclohexanol parchloroate To a solution o~ 1-diallylsulfoniomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclo-hexanediol perchlorate (143 mg) in dichloromethane (2 ml) was added dropwise, which was stirred for 30 minutes. To the reaction mixture was added water to suspend the reaction, which was subjected to extraction with ethyl acatate. The organic layer was washed with a saturated aqueous saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (carrier 15 g, developing solvent: chloroform-methanol = 20:1) to give l-diallylsulfoniomethyl-4-(N-chloroacetyl-carbamoyloxy)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol perchlorate (100 mg: yield 56%).
NMR spectrum (~ value; CD30D): 1.45(3H,s), 1.69(3H,s), 1.75(3H,s), 1.55 to 2.60(7H,m), 3.11(1H,m), 2~ 3~
g2 3.34~3H,s), 3.45(1H,m), 3.90 to 4.40(6H,m), 4.43(2H,s), 5.25(lH,m), ~.47(lH,m), 5.55 to 6.20(6H,m).
[a]D4-10.7 (c 0.21, CHC~3).
Elemental Analysis fox C2s~l3sNIoscl2:
Calcd. C:~8.70%, ~1:6.38%, N:2.27%, Found C:48.46~, H:6.67%, N:2.03%.
Example 6~
1-Dibenzylsulfoniomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol perchlorate Likewise in Example 66, from 1-benzylthiomethyl-2-~ epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy~
cyclohexanediol (300 mg) was obtained 1-dibenzyl-sulfoniomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy~ -cyclohexanediol perchlorate (145 mg: yield 33~) as colorless powder.
NMR spectrum (~ value; CD30D): 1.41(3H,s), 1.69(3H,s), 1.75(3H,s), 1.45 to 2.60(7H,m), 3.13(1H,m), 3.22(2H,m), 3.31(3H,s), 4.15(2H,m), 4.47(1H,d,13Hz), 4.71(1H,d,13Hz), 4.76(1H,d,13Hz), 4.98(1H,d,13Hz), 5.23(lH,m), 7.47(10H,m).
Example 69 l-Dibenzylsulfoniomethyl-4-(N-chloromethyl-carbamoyloxy)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol perchlorate Likewise in Example 67, from l-dibenzylsulfonio-methyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol perchlorate (120 mg) was obtained 1-dibenzylsulfoniomethyl-4-(N-chloromethylcarbamoyloxy)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol perchIorate (100 mg:
yield 69%) as colorless powder.
NMR spectrum (~ value; CD30D): 1.41(3H,s), 1.69(3H,s~, 1.74(3H,s), 1.55 to 1.90(4H,m), 2.10 to 2.60(3H,m), 3.04(1H,t,6Hz), 3.30(3H,s), 3.36(2H,m), ~3 ~ "
4.15(1H,d,12Hz~, 4.41(2H,s), 4.55(1H,d,13Hz), 4.74(1H,d,13Hz), 4.80(1H,d,13Hz), 4.98(1H,d,13Hz), 5.22(lH,m), 5.36(lH,m), 7.48(10H,m).
[a]D3-36.4 (c 0.20, CHCl3) Elemental Analysis for C33H~,3NQIoSCl3:
Calcd. C:55.31~, H:6.05~, N:1.95%, Found C:55.66%, H:6.17%, N:2.12%~
Example 70 4-Carbamoyloxy-2-(1 r 2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-dimethylsulfoniomethyl-cyclohexanol iodide Likewise in Example 13, from 4-O-carbamoyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methyl-thiomethyl-1,4-cyclohexanediol (240 mg) was obtained 4-carbamoyloxy-2-(ll2-epoxy-l~5-dimethyl 4-hexenyl)-3-methoxy-1-dimethylsulfoniomethyl-cyclohexanol iodide (282 mg: yield 85%) as colorless powder.
NMR spectrum (~ value; CD30D): 1.46(3H,s), 1.69(3H,s), 1.75(3H,s), 1.65 to 1.90(4H,m), 2.10 to 2.60(3H,m), 3.00(3H,s), 3.06(3H,s), 3.10(1H,t,6Hz), 3.34(3H,s), 3.41(1H,m), 3.73(1H,d,13Hz), 4.04(lH,d,13Hz), 5.25(2H,m).
~26 43 3O (c 0.21, CHC~3)-Elemental Analysis for Cl9H34NO5SI:
Calcd. C:44.27%, H:6.65%, N:2.72%, Found C:44.58~, H:6.87%, N:2.77%.
Example 71 l-Benzylmethylsulfoniomethyl-4-carbamoyloxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenylj-3-methoxycyclohexanol bromide Llkewise in Example 13, from 4-O-carbamoyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methyl-thiomethyl-1,4-cyclohexanediol (200 mg) was ob~ained 1-benzylmethylsulfoniomethyl-4-carbamoyloxy-~-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol bromide (240 mg: yield ~2%) as colorless powder.
NMR spectrum (~ value; CV30D): 1.43(1.5H,s), 1.44(1.5H,s), 1.68(3~1,s), 1.74(3H,s), 1.50 to 1.90(4H,m), 2.10 to 2.60(3H,m), 2.~1(1.5}1,s), S 2.9~(1.5H,s), 3.0~(1E~,t,6Hz), 3.31(1.5H,s), 3.33(1.5H,~), 3.40(1H,m), 3.57(0.5H,d,13Hz), 3.59(0.5H,d,131~z), 4.67(0.SH,d,13Hz), 4.74(lH, B ), 4.95(0.5H~d,13Hz), 5.23(2H,m).
~ ~ ~ 23 _ 36.4 (c 0.20, CHC~ 3 ) .
Elernental Analysis for C25H3aNO5SBr:
Calcd. C:55.14%, H:7.03%, N:2.57~, Found C:55.16~, H:7.32%, N:2.63%.
Example 72 4-(2-Chloroethylcarbamoyloxy)-2-(1,2-epoxy-1,5-dimethyl-~-hexenyl)-3-methoxy-1-methylthiomethylcyclohexanol To a solution of 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-methylthiomethyl-1,4-cyclohexanediol (1.00 g) and dimethylaminopyridine (185 ml) in dichloromethane (10 ml) was added dropwise 2-chloroethylisocyanate (0.52 ml), which was stirred overnight. To the reaction mixture was added water to suspend the reaction, ~hen the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, then the residue was purified by means of a silica gel column chromatography (carrier 50 g, developing solvent :
ethyl acetate - hexane = 1~4) to give 4-(2-chloroethylcarbamoyloxy)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methyl~hiomethylcyclohexanol (912 mg: yield 69~) as colorless powder.
NMR spectrum (~ value; CDC~3): 1.47(3H,s), 1.66(3H,s), 1.74(3H,s), 1.55 to 1.90(4H,m), 2.20(3H,s), 2.05 to 2.60(3H,m), 2.95(3H,m)~ 3.30(1X,m), 3.32(3H,s), s~ ~ ~
3.45 to 3.70(4H,m), 5.20(2H,m).
Example 73 4-(2-Chloroethylcarbamoylox~)-2-~1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-dimethylsulfoniomethylc~clohexanol iodide Likewise in E:xample 13, from 4-(2-chloroethylcarbamoyloxy)-2-(1,2-epoxy-1,5-dime~hyl-4-hexenyl)-3-methoxy-1-methylthiomethylcyclohexanol (150 mg) was obtained 4-(2-chloroethylcarbamoyloxy)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-dimethylsulfoniomethylcyclohexanol iodide (140 mg:
yi.eld 70%) as colorless powder.
NMR spectrum (~ value; CD30D): 1.46(3H,s), 1.69(3H,s), 1.75(3H,s), 1.65 to 1.90(4H,m), 2.I0 to 2.60(3~I,s), 2.99(3~,s)r 3.06(3~,s), 3.10(1Hrm), 3.33(3H,s), 3.35 to 3.65(5H,m), 3.71(1H,d,].4Hz), 4.04(1H,d,14Hz)r 5.25(1Hrm), 5.31(1H,m).
Example 74 1-Benzylmethylsulfoniomethyl-4-chloroacetylcarbamoyloxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3~methoxycyclohexanol tetrafluoroboxate In dichloromethane (1 ml) were dissolved 1-benzylthiomethyl-4-chloroacetylcarbamoyloxy-2~(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol (200 mg) and methyl iodide 10.24 ml).
To the solution was added silver tetrafluoroborater and the mixture was stirred for 8 hours at room temperature. Insolubles were filtered off, and the solvent was distilled off under reduced pressure. The residue was pulverized with ether to give 1-benzylmethylsulfoniomethyl-4-chloroacetylcarbamoyloxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol tetrafluoroborate (73 mg: yield30%) as colorless powder.
2~ J7~3~' - 96 ~
N~R spectrum (~ value; CD30D): 1.41(1.5H,s), 1.42(1.5H,s), (1.68(1.5H,s), 1.75(3H,s), 1.60 to 2.60(7H,m), 2.80(1.5H,s), 3.00(1.5H,s), 3.11(1H,t,6Hz), 3.32(1.5H,s), 3.34(1.5H,s), 3.~5(2H,m), 2.90 to 4.15(1H,m), 4.42(1H,s), 4.43(1~,s), 4.66(0.5H,d,13Hz), 4.70(1~1,s), 4.94(0.5}l,d,13}Iz), 5.22(1H,m), 5.45(1H,m).
[a]D~-23.3 (c 0.21, cHc~e3).
Example 75 1-Benzylmethylsuloniomethyl-4-chloroacetylcarbamoyloxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol tosylate Silver oxide (37 mg) was suspended in ~cetonitrile (1 ml), to which was added p-toluenesulfonic acid .
lS monohydrate (61 ml), and the mixture was stirred for 5 minutes. T~ the resultant was then added 1-benzylmethylsulfoniomethyl-4-chloroacetylcarbamoyloxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol bromide (200 m~). The mixture was stirred for further 30 minutes, then insolubles were filtered o~f. The solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (carrier 4 g, developing solvent : chloroform-methanol = 20:1) to give 1-benzylmethylsulfoniomethyl-4-chloroacetylcarbamoyloxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol tosylate (67 mg: yi21d 29%) as colorless powder.
NMR spectrum (~ value; CD30D): 1.41(1,5H,s), 1.42(1.5H,s), 1.68(1.5H,s), 1.75(3H,s), 2.37(3H,s), 1.60 to 2.60t7H,m), 2.80(1.5H,s), 3.00(1.5H,s), 3.11(1H,t,6Hz), 3.32(1.5H,s), 3.34(1.5H,s), 3.45(2H,m), 3.90 to 4.15(1H,m), 4.42(1H,s), 4.43(1H,s), 4.66(0.5H,d,13Hz), 4.70(1H,s), 4.94(0.5H,d,13Hz), 5.22(1H,m), 5.45(1H,m), 7.23(2H,d,8Hz), 7.72(2H,d,SHz).
~/~2~3~G
Example 76 l-Benzylmethylsulfoniomethyl-4-chloroacetylcarbamoyloxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol hydrogen L-tartrate S Likewise in Example 75, ~rom l-benzylmethyl-sulfoniomethyl-4-chloroacetylcarbamoyloxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol bromide (200 mg) was obtained 1-benzylmethylsulfoniomethyl-4-chloroacetylcarbamoyloxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol hydrogen L-tartrate (126 mg: yield 56%) as colorless powder.
NMR spectrum (~ value; CD30D): 1.42(1,5H,s), 1.43(1.5H,s), 1.67(1.5H,s), 1.74(3H,s), 1.60 to 2.60(71I,m), 2.81(1.5H,s), 3.00(1.5H,s), 3.11(1H,t,6Hz), 3.33(15H,s), 3.35(1.5H,s), 3.45(2H,m), 3.90 to 4.15(1H,m), 4.41(2H,s), 4.43(1H,s), 4.44(1H,s), - 4.66(0.5H,d,13Hz), 4.70(1H,s), 4.94(0.5H,d,13Hz), 5.22(lH,m), 5.45(lH,m).
[o~]24 28 4 (c 0.20, CHC~3).
Elemental Analysis for C3lH44NOl2SC1.1.5H2O
Calcd. C:51.91%, H:6.61%, N:1.95%, Found C:51.91%, H:6.70%, N:1.99%.
Example 77 1-Benzylmethylsulfoniomethyl-4-chloroacetyl-carbamoyloxy-2-(1,2-ep~xy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol hydrogen succinate Likewise in Example 75, from l~benzylmethyl-sulfoniomethyl-4-Chloroacetylcarbamoyloxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol bromide (200 mg) was obtained 1-benzylmethylsulfoniomethyl-4-chloroacetylcarbamoyloxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol hydrogen succinate (102 mg: yield 48%) as colorless po~der.
NMR spectrum (~ value: CD30D): 1.42(1.5H,s), 1.43(1.5H,s), 1.68(1.5H,s), 1.74(3H,s), 2.51t4H,s), 2 ~
1.60 to 2.60(7H,m), 2.80(1.5H,s), 3.00(1.5H,s), 3.ll(1H,t,6Hz), 3.32(1.5H,s), 3.34(1.5H,s), 3.45(2H,m), 3.90 to 4.15(1H,m), 4.42(2H,s), 4.42(1H,s), 4.43(1H,s), ~.66(0.5H,d,13Hz), 4.70(1H,s), 4.94(0.5H,d,13Hz), 5.22(lH,m), 5.45(lH,m).
~]D -29.7 (c 0.22, C~ICQ3).
Elemental Analysls for C3lH44NOloscl~H2o :
Calcd. C:55.06%, H:6.86~, N:2.07%, Found C:55.28%, H:6.65%, N:1.84%.
Example 78 l-Benzylmethylsulfoniomethyl-4-chloroacetylcarbamoyloxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol hydrogen oxalate Likewise in Example 75, ~rom l-benzylmethyl-sulfoniomethyl-4-chloroacetylcarbamoyloxy-2-(1,2-epoxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl) 3-methox-ycyclohexanol bromide (200 mg) was obtained 1-benzyl-methylsulfoniomethyl-4-chloroacetylcarbamoyloxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol hydrogen oxalate (151 mg: yield 74%) as colorless powder.
NMR spectrum (~ value; CD30D): 1.42(1.5H,s), 1.43(1.5H,s), 1.68(1.5H,s), 1.74(3H,s), 1.60 to 2.60(7H,m), 2.80(1.5H,s), 3.00(1.5H,s), 3.11(1H,t,6Hz), 3.32(1.5H,s), 3.34(1.5H,s), 3.45(2H,m), 3.90 to 4.15(1H,m), 4.42(2H,s), 4.42(1H,s), 4.43(1H,s), 4.66(0.5H,d,13Hz), 4.70(1H,s), 4.94(0.5H,d,13H2), 5.22(1H,m), 5.45(1H,m).
[~]D4-28.4O (c 0.21, CHCQ3).
Elemental Analysis for C2sH4oNoloscl~H2o Calcd. C:53.74%, H:6.53%, N:2.16%, Found C:54.49%, H:6.41%, N:2.10%.
Example 79 2-(1,2-Epoxy-1,5-dimethyl-4-hexenyl)-1-(2-~ 3~3t~
. 99 _ hydroxymethylbenzyl~thiomethyl-3-methoxy-1,4-cyclohexanedlol To an about 14~ methanol solution (6 ml) of sodium methoxide were added, under ice-cooling, 2-mercaptomethylbenzylalcohol (655 m~ and fumagillol (1.00 g). The mixture was stirred ~or one hour at room temperature, to which was added water to suspend the reaction. The product was extracted with ethyl acetate, The extrac~ solution was washed with a saturated aqueous solution o~ sodium chloride, then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (carrier 30 g, developing solvent :
lS ethyl acetate - hexane = 2:1) to give 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(2-hydroxymethylbenzyl)-thiomethyl-3-methoxy-1,4-cyclohexanediol (1.43 g :
yield 92%) as a colorless oily substance.
NMR spectrum (~ value; CDC~3): 1.39(3H,s), 1.66(3H,s), 1.75(3H,s), 1.55 to 1.85(4H,m), 2.00 to 2.55(3H,m), 2.84(1H,d,13Hz), 2.93(1H,d,13Hz), 2.94(1H,t,6Hz), 3.28(1H,m), 3.32(3H,s), 3.86(1H,d,13Hz), 3.96(1H,d,13Hz), 4.20(1H,m), 4.77(2H,br d,6Hz), 5.19(1H,m), 7.20 to 7.50(4H,m).
Example 80 2-(1,2-Epoxy-1,5-dimethyl-4-hexenyl)-1-(2-methanesulfonyloxymethylbenzyl)thiomethyl-3-meth 1,4-cyclohexanediol In dichloromethane (O.S ml) were dissolved 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(2-hydroxymethyl-benzyl)thiomethyl-3-methoxy-1,4-cyclohexanediol (100 mg) ~nd triethylamine (64 ~1). To the solution was added dropwise, under ice-cooling, methanesulfonylchloride (20 ~1). The mixture was stirred for 15 minutes, to which was added water to $ ~
suspend the reaction. The product was extracted with ethyl acetate. The extract solution was washed with a saturated aqueous sol~ltion of sodium chloride, which was then dried over anhydrous magnesium sulfate. The solvent was distilled of~ under reduced pressure. The residue was purified by means o~ a sili~a gel column chromatography (carrier 10 g, developing solvent: ethyl acetate - hexane = 2:1) to give 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(2-methanesulfonyl-oxymethylbenzyl)thiomethyl-3-methoxy-1,4-cyclohexanediol (98 mg: yield 83%) as a colorless oily product.
NMR spectrum (S value; CDC~3): 1.40(3H,s), 1.67(3H,s), 1.74(3H,s), 1.45 to 1.90(4H,m), 2.00 to 2.55(3H,m), 2.89(2H,s), 2.93tlH,t,6Hz), 2.95(3H,s), 3.27(1H,m), 3.33(3H,s), 3.85(1H,d,13Hz), 3.96~lH,d,13Hz), 4.21(lH,m), 5.20(lH,m), 5.42(1H,d,12Hz), 5.49(1H,d,12Hz), 7.25 to 7.50(4H,m).
Example 81 2-(1,2-Epoxy-1,5-dimethyl-4-hexenyl)-(1,3-dihydrobenzo[c~thiophen-2-ylio)methyl-3-methoxy-1,4-cyclohexanediol mesylate In dichloromethane (1 ml) was dissolved 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-t2-methanesulfonyl-oxymethylbenæyl)thiomethyl-3-methoxy-1,4-cyclohexanediol (900 mg). The solution was stirred for 24 hours at 30C. The solvent was distilled off under reduced pressure. The residue was pulverized with ether to give 2-(1 r 2-epoxy-1,5-dimethyl-4-hexenyl)-1-(1,3-dihydrobenzo[c]thiophen-2-ylio)methyl-3-methoxy-1,4-cyclohexanediol mesylate (889 mg: yield 98%) as colorless powder.
NMR spectrum (~ value; CD30D): 1.28(3H,s), 1.63(3H,s), 1.72(3H,s), 1.50 to 2.45(7H,m), 2.70(3H,s), 3.02(1H,m), 3.34(3H,s), 3.40(1H,m), 3.45(1H,d,13Hz), 3.89(1H,d,13~z), 4.78(1H,d,14Hz), 4.95 to 5.25(4H,m), 5.49(1H,m), 7.40 to 7.60(4H,m).
Example 82 4-(N-Chloraacetylcarbamoyloxy)-2-(1,2-epoxy-1,5-d.imethyl-4-hexenyl)-1-(1,3-dihyd.robenzo~c]thiophen-2-ylio)methyl-3-methoxycyclohexanol chloride In dichloromethane (2 ml) was dissolved 2-(1,2-epoxy-1,5 dimethyl-4-hexenyl)-1-(1,3-10 dihydrobenzo[c]thlophen-2-ylio)methyl-3-methoxy-1,4-cyclohexanediol mesylate (500 mg). To the solution was added dropwise, under ice-cooling, chloroacetylisocyanate (0.25 ml). The mixture was stirred for 15 minutes, to which was added water to 15 suspend the reaction. The product was extracted with ethyl acetate. The extract solution was dried over anhydrous magnesium sulfate, then the solvent was distilled off unde.r reduced pressure. The residue was purified by means of a silica gel column chromatography 20 (carrier 40 g, developing solvent : chloroform-methanol = 20:1) to give 4-(N-chloroacetylcarbamoyloxy)-2-(1,2-epox~-1,5-dimethyl-~-hexenyl)-1-(1 t 3-dihydrobenzo[c]thiophen-2-ylio)methyl-3-m-ethoxycyclohexanol chloride (88 mg: yield 13%) as 25 colorless powder.
NMR spectrum (~ value; CD30D): 1.28(3H,s), 1.63(3H,s), 1.71(3H/s), 1.50 to 2.45(7H,m)~ 3.02(1H,m), 3.33(3H,s), 3.51(1H,m), 3.52(1H,d,13Hz), 3.93(1H,d,13Hz), 4.23(2H,s), 4.86(1H,d,16Hz), 5.00 to 30 5.25(4H,m), 5.49(1H,m), 7.40 ~o 7.60(4H,m).
[~]D22-36.8 (c 0.22,CHC~3).
Elemental AnalysiS for C27H37NO6SC12-H2O:
Calcd. C:54.73%, H:6.63%, N:2.36%, Found C:54.65%, H:6.64~, N:2.40%.
Example 83 f~
2-(1,2-Epo~y-1,5-dimethyl-4-hexenyl)-1-(4-hydroxybutylyl)thiomethyl-3-methoxy-1,4-cyclohexanediol Likewise in Example 79, 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(2-hydroxybutylyl)thiomethyl-3-methoxy-1,4-cyclohexanediol was obtained a5 a colorless oily product (yield 79~).
NMR spectrum (~ value; CDC~3~: 1.46(3H,s), 1.67(3H,s), 1.75(3H,s), 1.45 to 1.90(8H,m), 2.00 to 2.70(5H,m), 2.89(2H,s), 2.97(1H,t,6Hz), 3.28(1H,m), 3.35(3H,s), 3.66(2H,m), 4.21(1H,m), 5.20(1H,m).
Example 84 2-(1,2-Epoxy-1,5-dimethyl-4-hexenyl)-1-(4-methanesulfonyloxybutylyl)thiomethyl-3-methoxy-1,4-cyclohexanediol Likewise in Example 80, 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(4-methanesulfonyloxybutylyl)thiomethyl-3-methoxy-1,4-cyclohexanediol as a colorless oily product (yield 92%) NMR spectrum (~ value; CDC~3): 1.46(3H,s), 1.67(3H,s), 1.74(3H,s), 1.45 to 1.95(4H,m), 2.00 to 2.55(3H,m), 2.64(2H,t,7Hz), 2.90(2H,s), 2.99(1H,t,6Hz), 3.02(3H,s), 3.27(1H,m), 3.34(3H,s), 4.23(1H,m), 4.25(2H,t,6Hz), 5.19(1H,m).
Example 85 2-(1,2-Epoxy-1,5-dimethyl-4-hexenyl)-3-methox~-1-~1-tetrahydrothienylio)methyl-1,4-cyclohexanediol mesylate Likewise in Example 81, 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-(1-tetrahydrothienylio)methyl-1,4-cyclohexanediol mesylate was obtained as colorless powder (yield 100%).
~MR spectrum (~ value; CD30D): 1.43(3H,s), 1.69(3H,s), 1.75(3H,s), 1.55 to 2.55(11H,m), 2.70(3H,s), 3.13(1H,m), 3.35(3H,s), 3.40 to 4.00(7H,m), 4.27(lH,m), 5.24(lH,m).
~ ~ 2 '~
Example 86 4-(N-Chloroacetylcarbamoyloxy)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-(1-tetrahydrothienylio)methylcyclohexanol chloride Likewise in Example 82, ~-(N-chloroacetyl-carbamoylo.~y)-2-(1,2-epoxy-1,5-dimethyl-~-he~enyl)-3-methoxy-l-(1-~etrahydrothienylio)methylcycl~hexanol chloride was obtainec~ as colorless powder (yield 95%).
NMR spectrum (~ value; CD30D)~ 3(3H,s), 1.68(3H,s), 1.75(3H,s), 1.60 to 2.55(11H,m), 3.12(1H,t,SHz), 3.34(3H,s), 3.~0 to 4.0S(7H,m), 4.44(2H,s), 5.23(1H,m), 5.47(1H,m).
[~]22-46.8 (c 0.20, CHC~3).
Elemental Analysis for C23H37NO8SC12.1.5H2O
Calcd. C:49.91~, H:7.28%, N:2.58%, Found C:50.07%, H:7.29%, N:2.85%.
Example 87 1-(2-Chloromethylbenzyl)thiomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol In dimethylformamide (0.5 ml) ware dissolved 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(2-hydroxymethylbenzyl)thiomethyl-3-methoxy-1,4-cyclohexanediol (100 mg) and trie~hylamine (64 ~ o the solution was added, under ice-cooling, lithium chloride (21 mg). To the mixture was added dropwise~
methanesulfonyl chloride (20 ~1), which was stirred for 3 hours, then the reaction was suspended by the addition of water. The product was extracted with ether, and the extract solution was washed with 2 saturated aqueous solution of sodium chloride, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (carrier 10 g, developing solvent ~ 3 : ethyl acetate - hexane =1:2) to give 1-(2-chloromethylbenzyl)thiomethyl-2-(1,2-epoxy-1,5-dimet-hyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol (70 mg:
yield 67~) as a colorless oily product.
NMR spe~trum (~ value; CDC~3): 1.~0(3H,s), 1.66(3H,s), 1.74(3~1,s), 1 45 to 1.90(4H,m), 2.00 to 2.55(3H,m), 2.89(2H,s), 2.96(lH,t,6~Iz), 3.27(lH,m), 3.33(3H,s), 3.90(1H,d,13Hz), 3.99(1H,d,13Hz), 4.21(1H,m), 4.76(1H,d,12Hz), 4.83(1H,d,12Hz), 5.20(lH,m), 7.20 to 7.40(4H,m).
Example 88 4-(N-Chloroacetylcarbamoyloxy)-1-(2-chlorometh~lbenzyl)thiomethyl-2-(l~2-epoxy-lr5 dimethyl-4-hexenyl)-3-methoxycyclohexanol In dichloromethane (1.5 ml) was dissolved 1-(2-chloromethylbenzyl)thiomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol (300 mg). To the solution was added dropwise, under ice-cooling, chloroacetylisocyanate (84 ~1). The mixture was stirred for 15 minutes, to which was added water to suspend the reaction. The product was extracted with ethyl acetate. The extract solution was washed with a saturated aqueous solution of sodium chloride, followed by drying over anhydrous magnesi~m sul~ate. The solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (carrier 30 g, developing solvent :
methyl acetate - hexane = 1:2) to give 4-(N-chloroacetylcarbamoyloxy)-1-(2-chloromethylbenzyl)-thiomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol (302 mg: yield 79%) as colorless powder.
NMR spectrum (~ value; CDC~3): 1.41(3H,s), 1.66(3H,s), 1.73(3H,s), 1.50 to 1.90(4H,m), 2.00 to 2.55(3H,m), 2.87(1H,d,13Hz), 2.92(1H,t,6H~), 2.98(1H,d,13Hz), 3.29(1H,m), 3.30(3H,s), 3.91(1H,d,13Hz), 4.01(1H,d,13Hz), 4.50(2H,s), 4.76(lH,d,12Hz), 4.84(1H,d,12Hz), 5.17(1H,m), 5.43(lH,m), 7.20 to 7.40(4~I,m).
~a]22-33.4 (c 0.20, CHC~3).
El~mental Analysis for C27H37NO6SC12 Calcd. C:56.44%, H:6.49%, N:2.44%, Found C:56.23%, H:6.55~, N:2.19%
Example 89 4-Carbamoyloxy-1-(2-chloromethylbenzyl)thiomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol In methanol (2 ml) was dissolved 4-(N~
chloroacetylcarbamoyloxy)-1-(2-chloromethylbenzyl)-thiomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol (193 mg). To the solution was added a standard buffer solution (2 ml) of pH 10, and the mixture was stirred for 5 hours. To the reaction mixture was added water, then the product was extracted with ethyl acetate. The extract solution was washed with a saturated aqueous solution of sodium chloride, which wa9 then dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure,then the residue was purified by means of a silica gel column chromatography (carrier 30 g, developing solvent: methyl acetate - hexane = 1:2) to give 4-(carbamoyloxy-1-(2-chloromethylbenzyl)thiomethyl-2-(1,2-epoxy-l,S-dimethyl-4-hexenyl)-3-methoxycyclohexanol (139 mg :
yield 83%) as a colorless oily product.
NMR spectrum (~ value; CDC~3): 1.42(3Hjs), 1.66(3H,s), 1.74(3H,s), 1.45 to 1.90(4H,m), 2.00 to 2.55(3H,m), 2.87(1H,d,13Hz), 2.94(1H,t,6Hz), 2.98(1H,d,13Hz), 3.27(1H,m), 3.32(3H,s), 3.91(1H,d,13Hz), 4.01(1H,d,13Hz), 4.66(2H,br s), ~ 106 -4.76(1H,d,12Hz), 4.84(1H,d,12Hz), 5.18(1H,m), 5.31(lH,m), 7.20 to 7.40(~H,m).
[~ 22 -24.7 (c 0.20, CHCR3).
Example 90 l-Benzylmethylsulfon.iomethyl-~-chloroacetylcarbamoyloxy-2-(1,2-epoxy-1,5-dimethyl--4-hexenyl)-3-methoxycyclohexanol hydrogen I.-malate L.ikewise in Example 75, from 1-benzylmethylsulfoniomethyl-4-chloroacetylcarbamoyloxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol bromide (200 mg) was obtained 1-benzylmethylsulfoniomethyl-4-chloroacetylcarbamoyloxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol hydrogen Il-malate (120 mg: yield 55%) as colorless powder.
NMR spectrum (~ value; CD30D): 1.42(1.5H,s), 1.43(1.5H,s), 1.68(1.5H,s), 1.74(3H,s), 1.60 to 2.60(7H,m), 2.52(1H,dd,7Hz,16Hz), 2.79(1H,dd,6Hz,16Hz), 2.80(1.5H,s), 3.00(1.5H,s), 3.11(1H,t,6Hz), 3.33(1.5H,s), 3.35(1.5H,s), 3.45(2H,m), 3.90 to 4.15(1H,m), 4.29(1H,dd,6Hz,7Hz), 4.42(1H,s), 4.43(1H,s), 4.66(0.5H,d,13Hz), 4.72(1H,s), 4.94(0.SH,d,13Hz), 5.22(lH,m), 5.45(lH,m).
[~]24-11.3 (c 0.21, CHC~3).
Elemental Analysis for C31H44NOl1SC1.1.5H2O:
Calcd. C:53.10%, H:6.76%, N:2.00%
Found C:53.21~, H:6.55%, N:2.30%
Example 91 4-(2-Benzothiazolylthio)thioacetylcarbamoyl-l-chloromethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol O-Chloroacetylcarbamoyl fumagillol (200 mg) was dissolved in dimethylformamide (2 ml). To the solution was added 2-mercaptobenzothiazol.sodium salt (141 mg), and the mixture was stirred for 30 minutes. To the reaction mixture was dilu~ed with i.sopropylether (50 ml), which was washed with a saturated aqueous solution o~ sodium hydrogencarbonate and a saturated a~ueous solution of sodium chloride, followed by drying over anhydrous ma~nesium sulfate. The solvent was distilled ofE under reduced pressure. The residue was di.ssolved in metharlol (5 ml), to which was added 1 N HCl (1 ml), and the mixture was stirred for 30 minutes. The raaction mixture was diluted with ethyl acetate (50 ml), which was diluted with a satura~ed aqueous solution of sodi~ chloride, a saturated aqueous solution of sodium hydrogen carbonate and further with a saturated aqueous solution of sodium chloride, followed by drying o~er anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure.
The residue was purified by means of a silica gel column chromatography (carrier 20 g, developing solvent: ethyl acetate - hexane = 1:1) to give 4-(2-benzothiazolylthio)thioacetylcarbamoyl~1-chloromethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)--3-methoxychlorohexanol (185 mg: yield 65%) as a colorless oily product.
NMR spectrum (~ value; CDCQ3): 1.42(3H,s), 1.65(3H,s), 1.74(3H,s), 1.45 to 1.90(4H,m), 2.00 to 2.55(3H,m), 2.94(1H,t,6Hz), 3.30(lH,m), 3.33(3H,s), 3.4g(1H,d,llHz), 3.73(1H,d,llHz) r 4.15(1H,d,lSHz), 4.24(lH,d,15Hz), 5.18(lH,m), 5.50(lH,m), 7.30 to 7.55(2H,m), 7.79(1H,d,8Hz), 7.94(1H,d,7Hz).
Elemental Analysis for C26H33N2O6S2Cl:
Calcd. C:54.87%, H:5.84%, N:4.92%r Found C:54.78%, H:5.75%, M:4.72%.
Example 92 2-(1,2-Epoxy-l,S-dimethyl-4-hexenyl)-1-(2-hydroxyethyl)thiomethyl-3-methoxy-1,4-cyclohexanediol ~ ~t~
Likewise in Example 79, 2-(1,2-epoxy-1,5~dimethyl-4-hexenyl)-1-(2-hydroxyethyl)thiomethyl-3-methoxy-1,4-cyclohexanediol (yield 51~) was obtained as colorless powder.
N~ spectrum (~ value; CDC~3): 1.46t3H,s), 1.67(3H,s), 1.75~3~,s), 1.50 to 1.90(4H,m), 2.00 to 2.55(3~1,m), 2.75 to 3.05(5H,m), 3.29(1H,m), 3.34(3H,s), 3.76(1H,q,6Hz), 4.22(1H,m), 5.20(1H,m).
Example 93 1-(4-Chlorobenzyl)thiomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol Likewise in Example 21, 1-(4-chlorobenzyl)thiomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol was obtained (yield ~6%) as a colorless oily product.
NMR spectrum (~ value, CDCQ3): 1.39(3H,s), 1.66(3H,s), 1.74(3H,s), 1.45 to 1.90(4H,m), 2.00 to 2.55(3H,m), 2.80(2H,s), 3.23(1H,t,6Hz), 3.23(1H,m), 3.33(3H,s), 3.71(1H,d,13Hz), 3.75(1~,d,13Hz), 4.20(1~,m), 5.18(lH,m), 7.26(4H,m).
Example 94 2-(1,2-Epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-4-methylthioacetylcarbamoyloxy-1-methylthiomethylcyclohexanol In dimethylformamide (3 ml) was dissolved 4-O-chloroacetylcarbamoyl-2-(1,2-epoxy-1,5-dimethyl-4-hex-enyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (500 mg). To the solution was added thiomethoxide (15 mg), and the mixture was stirred for one ho~x. The reaction mixture was diluted with ether (S0 ml), which was washed with a saturated aqueous solution of sodium chloride, ~ollowed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (carrier 25 g, developing solvent: ethyl acetate - hexane = 2:1) to give 2-(1,2-epoxy-1,5-dimethyl-~-hexenyl)-3-methoxy-4-methylthioacetylcarbamoyloxy-l-methylthiomethylc~clohexanol (407 mg: ~ield 79~) ascolorless powder.
NMR spectrum (~ value; CDC~): 1.47(3H,s), 1.66(3H,s), 1.73(3H,s), l.~S to 1.95(~H,m), 2.00 to 2.55(3H,m), 2.19(3H,s), 2.21(3H,s), 2.86(1H,d,13H~), 2.90(1~,t,6Hz), 2.98(1H,d,13Hz), 3.32(3H,s), 3.33(1H,m), 3.52(1H,d,lSHz), 3.63(1H,d,15Hz), 5.19(lH,m), 5.45(lH,m).
Example 95 4-Benzylthioacetylcarbamoyloxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethylcyclohexanol In dimethylformamide (2 ml) was suspended 60%
sodium hydride (67 mg), to which was added dropwise ~0 benzylmercaptan (O.lS ml). The mixture was stirred for 15 minutes, to which was then added ~-O-chloroacetylcarbamoyl-2-(1,2-epoxy-1,5-dimethyl-4-hex-enyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (500 mg). The mixture was stirred for further one hour. To the reaction mixture was added water to suspend the reaction, and the product was extracted with ether. The extract solution was washed with a saturated aqueous solution of sodium chloride, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under redused pressure, and the residue was purified by means of a silica gel column chromatography (carrier 25 g, developing solvent: ethyl acetate - hexane = 1:2) to give 4-benzylthioacetylcarbamoyloxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethylcyclohexanol (397 mg: yield 66%) as a colorless oily product.
NMR spectrum (~ value; CDCQ3): 1.47(3H,s), 1.66(3H,s), 1.73(3H,s), 1.50 to 1.90(4H,m), 2.00 to 2.55(3H,m), 2.21(3H,s), 2.86(lH,d,13Hz), 2.94(1H,t,6Hz), 2.98(1~1,d,13Hz), 3.32(3H,s), 3.33(lH,m), 3.44(lH,d,lSHz), 3.52(1H,d,15Hz), 3.~9(2EI,s), 5.19(lEI,m), S.43(1H,m), 7.20 ko 7.45(5I~,m).
E~ample 96 1-Bromomethyl-4-chloroacetylcarbamoyloxy-2-(1,2-epoxy-10 1,5-dime~hyl-4-hexenyl)-3-methoxycyclohexanol Likewise in Example 2, from 1-bromomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol (200 mg) was obtained 1-bromomethyl-4-chloroacetylcarbamoyloxy-2-(1,2-epoxy-1,5-dimethyl-4-15 hexenyl)-3-methoxycyclohexanol (178 mg : yield 63~) as colorless crystals, m.p. 111 to 112C.
NMR spectrum (~ value; CDC~3): 1.47(1H,m), 1.51(3H,s), 1.66(3H,s), 1.74(3H,s), 1.70 to 2.55(7H,m), 2.96(lH,d,6Hz), 3.29(lH,m), 3.32(3H,s), 20 3.45(1H,d,lOHz), 3.75(1H,d,lOHz), 4.51(2H,s), 5.18(lH,m), 5.45(lH,m).
[~]23 97 5 (c 0.20, CHC~3).
Elemental Analysis for Cl9H~9NO6SBrCl:
Calcd. C:47.27%, H.6.05%, N:2.90%
Found C:47.18%, H:6.07%, N:2.84%
Example 97 4-Amino-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(2~
hydroxymethylbenzyl)thiomethyl-3-methoxycyclohexanol To an about 7% methanol solution (2.01 ml) of sodium methoxide were added, under ice-cooling, a methanol solution (0.5 ml) of 2-mercaptomethylbenzylalcohol (165 mg~ and a methanol solution (0.5 ml) of 6-oxo-6-desoxyfumagillol (300 mg).
The mixture was stirred for one hour at room temperature, followed by addition of water to suspend the reaction. The reaction mixture was subjected to extraction with ethyl acetate. The 0xtract solution was washed with a saturated aqueous soluti.on of sodium chloride, -then dr.ied over anhydrous ma~nesium sulfate.
The solvent was distilled o~f under reduced pressure, and the residue was purified by means o~ a silica gel column chromatography (carrier 30 g, developing solvent: ethyl acetate - hexane = 2:1) to give 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(2-hydroxymethylbe-nzyl)thiomethyl-3-methoxy-4-oxocyclohexanol (397 mg:
yield 85%) as a colorless oily product.
NMR spectrum (~ value; CD~3): 1.39(3H,s), 1.66(3H,s), 1.73(1H,m), 1.74(3H,s), 2.00 to 2.55(4H,m), 2.40(1H,t,6Hz), 2.65 to 3.05(3H,m), 2.95(1H,d,6Hz), 3.3g(3H,s), 3.84(1H,d,12Hz), 3.92(2H,d,6Hz), 4.01(1H,m), 4.77(2H,d,6~Iz), 5.18(1H,m), 7.20 to 7.45(4H;m)-2-(1,2-Epoxy-1,5-dimethyl-4-hexenyl)-1-(2-hydroxymethylbenzyl)thiomethyl-3-methoxy-4-oxocyclohexanol (1.07 g) and ammonium acetate (1.86 g) were dissolved in methanol (25 ml). To the solution was added sodium cyanoborohydride (304 mg), and the mixture was stirred for one hour. The solvent was distilled off under reduced pressure, and the.residue was dissolved in ethyl acetate (100 ml). The solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (carrier 40 g, developing solvent: chloroform-methanol-NH40H
-20:1:0.1) to obtain 4-amino-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(2-hydroxymethylbenzyl)thiomethyl-3-methoxycyclohexanol (629 mg; yield 58%) as a colorless oily product.
NM~ spectrum (~ value; CDC~3): 1.35 to l.90(~H,m), 1.39(3Hrs), 1.66(3~,s), 1.74(3H,s), 2.05 to 2.55(3H,m), 2.90(2H,s), 2.96(1H,-t,6Hz), 3.25(1H,m), 3.2B(3H,s), S 3.52(1H,d,13Hæ), 3.99(2H,d,13Hz), 4.74(1H,d,12Hz), 4.81(lEI,d,12Hæ), 5.19(1H,m), 7.20 to 7.45(4H,m).
Example 98 4-(N'-chloroacetylureido)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(2-hydroxymethylbenzyl)thiomethyl-3-methoxycyclohexanol In dichloromethane (20 ml) was dissolved 4-amino-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(2-hydroxy-methylbenzyl)thiomethyl-3-methoxycyclohQxanol (629 mg).
To the solution was added dropwise, under ice-cooling, chloroacetyl isocyanate (0.22 ml). The mixture was stirred for 10 minutes, to which was then added water to suspend the reaction. The reaction product was extracted with ethyl acetate. The extract solution was washed with a saturated aqueous solution of sodium chloride and, then, dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by means o~ a silica gel column chromatography (carrier 30 g, developing solvent: ethyl acetate - hexane = 3:2) to a~ford 4-(N'-chloroacetylureido)-2-(1,2-epoxy-1,5-dimethyl-4-hex-enyl)-l-(2-hydroxymethylbenzyl)thiomethyl-3-methoxycyclohexanol (514 mg: yield 64%) as a colorless powdery product.
NMR spectrum (~ value; CDC~3): 1.40(3H,s), 1.45 to 2.55(6H,m), 1.65(3H,s), 1.73(3H,m), 2.65(1H,t,6Hz), 2.83(1H,d,13Hz), 2.96(1H,t,6Hz), 2.97(1H,d,13Hz), 3.30(3H,s), 3.35(1H,dd,4Hz,llHz), 3.86(1H,d,13Hz), 3.94(1H,d,13Hz), 4.15(2H,s), 4.47(1H,m), 4.75(1H,dd,6Hz,13Hz), 4.81(1H,dd,6Hz,13Hz), 5.17(1H,m), 7.20 to 7.45(4H,m), 8.25(2H,m).
Example 99 4-(N'-chloroacetylureido)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(2-methanesul~onyloxyJnethylbenzyl)t~liomethyl-3-me-thoxycyclohex~nol In dichloromethane (3 ml) were dissolved 4-(N'-chloroacetylureido)-2-(1,2 epoxy-l,S-dimethyl-4-hex-enyl)-1-(2-hydroxymethylbenz~l)thiomethyl-3-methoxycyclohexanol t514 mg) and triethylamine (0.33 ml). To the solution was added dropwise at -20C
methanesulfonyl chloride (96 ~Q). The mixture was stirred for 10 minutes, to which was added water to suspend the reaction. The reaction product was extracted with ethyl acetate. The extract solution was washed with a saturated aqueous solution o~ sodium chloride and, then, dried over anhydrous magnesium sulfate. The solvent was distilled o~ under reduced pressure to leave 4-(N'-chloroacetylureido)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(2-methanesulfonyloxymethylbenzyl)thiomethyl-3-me-thoxycyclohexanol (550 mg; yield 98%) as a colorless powdery product.
NMR spectrum (~ value; CDC~3): 1.40(3H,s), 1.65(3H,s), 1.73(3H,s), 1.45 to 1.95(4H,m), 2.00 to 2.55(3H,m), 2.81(1H,d,14Hz), 2.94(3H,s), 2.97(1H,d,14Hz), 2.98(1H,t,6Hz), 3.30(3H,s), 3.35(1H,m), 3.86(1H,d,13Hz), 3.96(1H,d,6Hz), 4.16(3H,br s), 4.48(1H,m), 5.26(1H,m), 5.46(2H,s), 7.15 to 7.55(4H,m), 8.42(1~,m).
Example 100 4-(N'-chloroacetylureido)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-l-(1,3-dihydrobenzo[c]thiophen-2-ylio)methyl-3-methoxycyclohexanol chloride In dichloromethane (2 ml) was dissolved 4-(N'-chloroacetylureido)-2-~1,2-epoxy-1,5-dimethyl-4-hex-enyl)-1-(2-methanesulfonyloxymethylbenzyl)thiomethyl-3-methoxycyclohexanol (450 mg). The solution was sti.rred Eor 24 hou~s ~t 30C. The solvent was distilled of under reduced pressure. To the residue was added water, to which was added sodium chloride to perform saltin~ out. The product was extracted with ethyl acetate. The extract solution was dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. To the residue was added ether to cause pulverization to give 4-(N'-chloroacetylureido)-2-(l~2-epoxy-l~5-dimethyl-4~hex-enyl)-1-(1,3-dihydrobenzo[c]thiophen-2-ylio)methyl-3-methoxycyclohexanol chloride (293 mg: yield 71%) as a colorless powdery product.
NMR spectrum (~ value; CD30~): 1.31(3H,s), 1.64(3H,s), 1.72(3H,s), 1.55 to 2~45(7H,m), 3.07(1H,t,7Hz), 3.31(3H,s), 3.52(1H,d,13Hz), 3.56(lH,dd,4Hz,lOHz), 3.91(lH,d,13Hz), 4.19(2H,s), 4.42(lH,m), 4.81(lH,d,16Hz), 4.95 to 5.25(4H,m), 7.40 to 7.60 (4H,m).
[~]22_ 31.8 (c 0.21, CHCQ3).
Elemental Analysis for C27H38N2O5SC12.0-5H2O :
Calcd.: C:55.66%, H:6.75%, N:4.81~, Cl:12.17%, S:5.50%
Found : C:55.50%, H:6.73%, N:4.63%, C1:11.65%, S:5.84%
Example 101 2-(1,2-Epoxy-1,5-dimethyl-4-hexenyl)-1-(3,4,5,6-tetrafluoro-2-hydroxymethylbenzyl)thiomethyl-3-methoxy-1,4-cyclohexanediol Likewise in Example 79, from fumagillol (249 mg) was obtained 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(3,4,5,6-tetrafluoro-2-hydroxymethylbenzyl)thiomethyl-3-methoxy-1,4-cyclohexanediol (350 mg: yield 77%) as a colorless oily product.
~R spectrum (~ value; CDC~3): 1.40(3H,s), r~
1.66(3H,s), 1.75(3H,s), 1.75(3H,s), 1.55 to 1.85(4H,m), 2.00 to 2.50(3H,m), 2.89(1H,d,13Hz), 2.92(1H,t,7Hz), 2.97(1H,d,13Hz), 3.20(1H,m), 3.31(3H,s), 3.~8(1~I,dd,2Hz,13Hz), 4.03(1H,dd,lHz,13Hz), 4.19(1H,m), 4.77(2H,m), 5.18(lH,m).
Example 102 2-(1,2-Epoxy-l,S-dimethyl-4-hexenyl)-1-(3,4,5,6-tetrafluoro-2-methanesulfonyloxymethylbenzyl)thiomethyl-3-methoxy-1,4-cyclohexanediol Likewise in Example 80, from 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(3,4,5,6-tetrafluoro-2-hydroxymethylbenzyl)thiomethyl-3-methoxy-1,4-cyclohe-xanediol (300 mg) was obtained 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(3,4,5,6-tetrafluoro-2-methanesulonyloxymethylbenzyl)thiomethyl-3-meth ,4-cyclohexanediol (330 mg: yield 95%) as a colorless oily product.
NMR spectrum (~ value; CDCQ3): 1.41(3H,s), l.S6(3H,s), 1.74(3H,s), 1.55 to 1.85(4H,m), 2.00 to 2.50(3H,m), 2.90(1H,d,13Hz), 2.97(1H,t,7Hz), 3.02(1H,d,13Hz), 3.08(3H,s), 3.25(1H,m), 3.94(1H,dd,2Hz,13Hz), 4.02(1H,dd,2Hz,13Hz), 4.21(1H,m), 5.19(1H,m), 5.46(1H,br s).
Example 103 2-(1,2 Epoxy-1,5-dimethyl-4-hexenyl)-1-(6-hydroxymethyl-3-cyclohexenylmethyl)thiomethyl-3-methoxy-1,4-cyclohexanediol Likewise in Example 79, from fumagillol (700 mg) was obtained 2-(1,2-epoxy-l,S-dimethyl-4-hexenyl)-1-(6-hydroxymethyl-3-cyclohexenylmethyl)thiomethyl-3-methoxy-1,4-cyclohexanediol (988 mg: yield 90%) as a colorless oily product.
NMR spectrum (~ value; CDCQ3): 1.46(3H,s), 2 ~
1.67(3H,s), 1.75(3H,s), 1.55 to 2.80(13H,m), 2.96(lH,d,13Hz), 2.98(1H,t,6Hz), 3.30(lH,m), 3.24(3H,s), 3.45 to 3.75(~H,m), 4.22(lH,m), 5.20(lH,m), 5.63(2H,hr s).
Example lO~
4-(N-chloraacetylcarbamoyloxy)-2-(1,2 epoxy-1,5-dimethyl-4-hexenyl)-1~(1,3,3a,4,7,7a-hexahydrobenzo[c]thiophen-2-ylio)methyl-3-methoxycyclohexanol chloride In dichloromethane (3 ml) were dissolved 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-l-(6-hydroxymethyl-3-cyclohexenylmethyl)thiomethyl-3-methoxy-1,4-cyclohexanediol (500 mg) and triethylamine (0.32 ml).
To the solution was added dropwise at -20C
methanesulfonyl chloride (92 ~). The mixture was warmed to room temperature, which was stirred for one hour. The mixture was then cooled on an ice-bath, to which was added dropwise chloroacetyl isocyanate (0.29 ml). The mixture was stirred for lO minutes, to which was then added water to suspend the reaction. To the reaction mixture was added sodium chloride to perform salting-out, followed by extraction with ethyl acetate.
The extract solution was dried over anhydrous magnesium sulfate. The solvent was then distilled o~f under reduced pressure. The residue was purified~by means of a silica gel column chromatography (carrier 20 g, developing solvent: chloroform-methanol = 15:1) to afford 4-(N-chloroacetylcarbamoyloxy)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(1,3,3a,4,7,7a-hexahydrobenzo[c]thiophen-2-ylio)methyl~3-methoxycyclohexanol chloride ~214 mg: yield 27%) as a colorless powdery product.
NMR spectrum (~ value; CD30D)~ 5(3H,s), 1.68(3H,s), 1.75(3H,s), 1.70 to 2.30(8H,m), 2.35 to 2.55(3H,m), 2.85 to 3.05(2H,m), 3.12(1H,t,6Hz), ~ ~ rJ ~
3.34(3H,s), 3.40 to 3.75(5H,m), 3.84(1H,dd,6Hz,13Hz), 4.13~1H,d,13Hz), 4.43(2H,s), 5.24(1H,m), 5.47(1H,m), 5.70(2H,br s).
Example 105 4-amino-2-(1,2 epoxy-1,5-dimekhyl-4-hexenyl)-1-(6-hydroxymethyl-3-cyclohexenylmethyl)thiomethyl-3-methoxycyclohexanol Likewise in Example 97, from 6-oxo-6-desoxyfumagillol, by way of 2~(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(6-hydroxymethyl-3-cyclohexenylmethyl)thiomethyl-3-methoxy-4-oxocyclohexanol, was obtained 4-amino-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(6-hydroxymethyl-3-cyclohexenylmethyl)thiomethyl-3-methoxycyclohexanol as a colorless oily product.
2-(1,2-epoxy-1,5-dimethyl-4-hexenyl) 1-(6-hydroxymethyl-3-cyclohexenylmethyl)thiomethyl-3-methoxy-4-oxocyclohexanol:
NMR spectrum (~ value; CDCl3): 1.46(3H,s), 1.67(3H,s), 1.74(3H,s), 1.65-2.85(13H,m), 2.85-3.10(4H,s), 3.41(3H,s), 3.45~3.75(2H,m), 3.87(1H,d,12Hz), 3.99(1H,dd,2Hz,8Hz), 5.19(1H,m), 5.63(2H,d,2Hz).
4-amino-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(6-hydroxymethyl-3-cyclohexenylmethyl)thiomethyl-3-methoxycyclohexanol:
NMR spectrum (~ value; CDCl3): 1.45(1.5H,s), 1.46(1.5H,s), 1.66(3H,s), 1.74(3H,s), 1.50-3.05(18H,m), 3.25(lH,m), 3.29(3H,s), 3.45-3.75(3H~m), 5.19(1H!m), 5.62(2H,br s).
Example 106 4-(N'-chloroacetylureido)-2-(1,2-epoxy-1,5-dimethyl-4 hexenyl)-1-(6-hydroxymekhyl-3-cyclohexenylmethyl~hiomethyl-3-methoxycyclohexanol Likewise in Example 98, from 4-amino-2-(1,2-epoxy-r3 ~ 118 ~
1,5-dimethyl-4-hexenyl)-1-(6-hydroxymethyl-3-cyclohexenylmethyl)thiomethyl-3-methoxycyclohexanol (870 mg) was obtained 4-(N'-chloroacet~lureido)-2-(1,2-epoxy-1,5-dimethyl-4-he~enyl)-1-(6-hydroxymethyl-3-cyclohexenylmethyl)thiomethyl-3-methoxycyclohexanol (588 mg: yield 53~) as a colorless oily product.
NMR spectrum (~ value; CDCl~): 1.46(1.5H,s), 1.48(1.5H,s), 1.66(3H,s), 1.7~(3H,s), 1.50-3.10(18H,m), 3.31(1.5H,s), 3.32(1.5H,s), 3.25-3.90(4H,m), 4.13(1H,s), 4.14(1~1,s), 4.50(1H,m), 5.17(1H,m), 5.62(2H,br s), 8.43(lH,m), 8.59(lH,m).
Example 107 4-(N'-chloroacetylureido)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(1,3,3a,4,7,7a-hexahydrobenzo~c]thiophen-2-ylio)methyl-3-methoxycyclohexanol chloride In dichloromethane (5 ml) were dissolved ~-(N'-chloroacetylureido)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(6-hydroxymethyl-3-cyclohexenylmethyl)thiomethyl-3-methoxycyclohexanol (500 mg) and triethylamine (0.25 ml). To the solution was added dropwise at -20C methanesulfonyl chloride (69 ~1). The mixture was warmed to room temperature, which was stirred for one hour. The solvent was distilled off under reduced pressure and the residue was dissolved in water. Insolubles were removed off by decantation and to the obtained supernatant liquid was added sodium chloride, followed by salting out. The product was extracted with ethyl acetate. The extr~ct solution was dried over anhydrous magnesium sulfate then the solvent was distilled o~f under reduced pressure. The residue was purified by means of a silica gel column chromatography (carrier 20 g, developing solvent : chloroform - methanol = 15:1) to give 4-(N'-chloroacetylureido)-2-(1,2-epoxy-l,S-dimethyl-4-hexenyl)-1-(1,3,3a,4,7,7a-hexahydrobenzo[c]thiophen-2-ylio)methyl-3-methoxycyclohexanol chloride ~290 mg: yield 56%) as colorless powder.
NMR spectrum (~ value; CD30D): 1.47(3H,s), 1.68~3H,s), 1.75(3H,s), 1.55-2.30(8H,m), 2.35-2.55(3H,m), 2.85-3.05(2H,m), 3.15(1H,t,6Hz), 3.33(3H,s), 3.50-3~65(5H,m), 3.70(1H,d,13Hz), 3.82(1H,dd,6Hz,13Hz), 4.13(1H,d,13Hz), 4.19(2H,s), 4.43(lH,m), 5.23(lH,m), 5.70(2H,br s).
Elemental Analysis for C27H42N2O5SC12-075H2O
Calcd. C:54.86%, H:7.42%, N:4.74%
Found C:54.95%, H:7.76%, N:5.00%
Claims (37)
1. A pharmaceutically acceptable cyclohexanol derivative or the general formula:
(I) [wherein:
A is halogen, , N?R1R2R3?X? , or (where X? is a counter anion; m is an integer of 0 or 1;
n is an integer of 0, 1 or 2; R1 and R2, taken separately, are each a hydrocarbon group or a hetarcyclic group; the hydrocarbon group is a member selected from the class consisting of C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C3-6cycloalkenyl, C7-13aralkyl and C6-10aryl; and the heterocyclic group is a member selected from the class consisting of 2-furyl, 2-thienyl, 4-thiazolyl, 4-imidazolyl, 4-pyridyl, 1,3,4-thiadiazol-2-yl and 5-tetrazolyl and the heterocyclic group may have a benzene, pyridine or cyclohexane ring condensed therewith; or R1 and R2, taken together with the adjacent nitrogen or sulfur atom to which they are attached, form a nitrogen or sulfur-containing hetero-cyclic ring which is selected from the class consisting of pyrrolidino, piperidino, piparazino, morpholino, tetrahydrothio-phen-1-yl and 1,4-thioxan-1-yl and which may have a benzene, pyridine, pyrazine, pyridazine, cyclohexane or cyclohexene ring condensed therewith) B is O or NR4 (where R4 is hydrogen, C1-6alkyl or C6-10aryl);
D is 2-methyl-1-propenyl or isobutyl; and E is hydrogen, a hydrocarbon group of the same meanings given above for R1 and R2 or acyl, the acyl is a member selected from the class consisting of C1-10alkanoyl, C7-10aroyl, 2-furoyl,
(I) [wherein:
A is halogen, , N?R1R2R3?X? , or (where X? is a counter anion; m is an integer of 0 or 1;
n is an integer of 0, 1 or 2; R1 and R2, taken separately, are each a hydrocarbon group or a hetarcyclic group; the hydrocarbon group is a member selected from the class consisting of C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C3-6cycloalkenyl, C7-13aralkyl and C6-10aryl; and the heterocyclic group is a member selected from the class consisting of 2-furyl, 2-thienyl, 4-thiazolyl, 4-imidazolyl, 4-pyridyl, 1,3,4-thiadiazol-2-yl and 5-tetrazolyl and the heterocyclic group may have a benzene, pyridine or cyclohexane ring condensed therewith; or R1 and R2, taken together with the adjacent nitrogen or sulfur atom to which they are attached, form a nitrogen or sulfur-containing hetero-cyclic ring which is selected from the class consisting of pyrrolidino, piperidino, piparazino, morpholino, tetrahydrothio-phen-1-yl and 1,4-thioxan-1-yl and which may have a benzene, pyridine, pyrazine, pyridazine, cyclohexane or cyclohexene ring condensed therewith) B is O or NR4 (where R4 is hydrogen, C1-6alkyl or C6-10aryl);
D is 2-methyl-1-propenyl or isobutyl; and E is hydrogen, a hydrocarbon group of the same meanings given above for R1 and R2 or acyl, the acyl is a member selected from the class consisting of C1-10alkanoyl, C7-10aroyl, 2-furoyl,
2-thenoyl, nicotinoyl, isonicotinoyl, C6-10arylsulfonyl, C1-6alkyl-sulfonyl, C2-7alkoxycarbonyl, C7-11aryloxycarbonyl, carbamoyl, thiocarbamoyl and sulfamoyl, wherein each of the hydrocarbon group defined above for R1 and R2, the heterocyclic group defined above for R1 and R2, the nitrogen- or sulfur-containing heterocyclic group defined above for R1 and R2 taken together, the C1-6alkyl defined above for R4, the C6-10aryl defined above for R4, the hydrocarbon group defined above for E and the acyl defined above for E may optionally have up to five substituents each independently selected from the class consisting of C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6hydroxy-alkyl, C3-6cycloalkyl, C3-6cycloalkenyl, C6-10aryl, amino, C1-6alkylamino, di-C1-6alkylamino, azido, nitro, halogen, hydroxyl, C1-4alkoxy, C6-10aryloxy, C1-6alkylthio, C1-6arylthio, cyano, carbamoyl, carboxyl, C1-4alkoxy-carbonyl, C7-11aryloxycarbonyl, carboxy-C1-4alkoxy, C1-6alkanoyl, (which may be substituted by halogen, C1-6alkylthio, C7-11aralkylthio, C6-10arylthio,or heterocycliothio, where the heterocyclic is defined above for R1 and R2), C3-6alkenoyl, C1-6thioalkanoyl (which may be substituted by heterocyclic-thio, where the heterocyclic is defined above for C1-6halogenoalkyl, 2-furyl, 2-thienyl, 4-thiazolyl, 4-imidazolyl, 4-pyridyl, 1,3,4-thiadiazol-2-yl, 1-methyl-5-tetrazolyl, 2-furoyl, 2-thenoyl, nicotinyl, isonicotinyl, 4-pyridylthio, 2-pyrimidylthio, 1,3,4-thiadiazol-2-ylthio, 1-methyl-5-tetrazolylthio, 2-benzothia-zolylthio and 8-quinolylthio, and the carbamoyl, thiocarbamoyl and sulfamoyl defined for E may have a nitrogen-containing hetrocyclic group selected from the class consisting of pyrrolidino, piperi-dino, morpholino, piperazin-1-yl, 4-methylpiperazin-1-yl and 4-phenylpiperazin-1-yl formed together with the nitrogen atom of the carbamoyl, thiocarbamoyl or sulfamoyl group;
provided that when A is chlorine, E is the hydrocarbon group or the acyl group(except for dinitrobenzoyl) or a pharma-ceutically acceptable salt thereof.
2. A compound according to Claim 1, wherein D is 2-methyl-1-propenyl; A is - S?R1R2?X?; and R1, R2 and X are as defined in claim 1.
provided that when A is chlorine, E is the hydrocarbon group or the acyl group(except for dinitrobenzoyl) or a pharma-ceutically acceptable salt thereof.
2. A compound according to Claim 1, wherein D is 2-methyl-1-propenyl; A is - S?R1R2?X?; and R1, R2 and X are as defined in claim 1.
3. A compound according to claim 2, wherein: R1 and R2, taken together with the sulfur atom to which they are attached, form a sulfur-containing hetrocyclic ring selected from the class consisting of tetrahydrothiophen-1-yl, 1,4-thioxan-1-yl, 1,3-di-hydrobenzo[c]thiophen-2-yl, 2,3-dihydrobenzo[b]thiophen-1-yl, 1,3,3a,4,7;7a-hexahydrobenzo[c]thiophen 2-yl, perhydrobenzo[c]-thiophen-2-yl, 1,2,4,5-tetrahydro-3-benzothiepin-3-yl, 1,3-di-hydrothieno[3,4-c]pyridin-2-yl, 5,7-dihydrothieno[3,4-b]pyrazin-6-yl, and 5,7-dihydrothieno[3,4-d]pyridazin-6-yl.
4. A compound according to claim 3, wherein the sulfur-containing heterocyclic rlng is 1,3-dihydrobenzo[c]thiophen-2-yl, tetrahydrothiophen-1-yl ar 1,3,3a,4,7,7a-hexahydrobenzo[c]thio-phen-2-yl .
5. A compound according to claim 2, wherein: R1 is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C3-6cyclo-alkenyl or C7-13aralkyl; and R2 is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3_6cycloalkyl, C3-6cycloalkenyl, C7-13aralkyl, C6-10aryl or a hetrocyclic group selected from the class consisting of 2-furyl, 2-thienyl, 4-thiazolyl, 4-imidazolyl, 4-pyridyl, 1,3,4-thiadiazol-2-yl and 5-tetrazolyl, and the cycloalky,the cycloalkenyl, the aryl and the aryl ring of the aralkylgroups may have up to five substituents selected from the class consisting of C1-6alkyl, C1-6hydroxyalkyl, amino, mono- or di-C1-6alkylamino, nitro, halogen, hydroxy, C1-4alkoxy, C1-6alkylthio, cyano, carbamoyl, carboxyl, C1-6alkanoyl , C1-6alkylsulfonyl, C1-6alkyl-sufonyloxy and C1-6alkylsulfonyloxy-C1-6alkyl; and the C1-6alkyl, C2-6alkenyl and C2-6alkynyl defined for R1 and R2 may be substit-uted by halogen, hydroxyl or C1-6alkylsulfonyloxy.
6. A compound according to claim 5, wherein R2 is other than the hetercyclic group.
7. A compound according to claim 5, wherein: A is dimethyl-sulfonio, ethylmethylsulfonio, benzylmethylsulfonio, (2-propynyl) methylsulfonio, allylmethylsulfonio, (4-bromobenzyl)methylsulfonio, (4-chlorobenzyl)methylsulfonio, (4 fluorobenzyl)methylsulfonio, (4-methylbenzyl)methylsulfonio, (3-bromobenzyl)methylsulfonio, (2-bromobenzyl)methylsulfonio, diallylsulfonio or dibenzylsulfonio.
8. A compound according to claim 1, wherein: A is -S-R2, -SO-R2 or ; D is 2-methyl-1-propenyl; and R2 is as defined in claim 1.
9. A compound according to claim 8, wherein: R2 is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C3-6cyclo-alkenyl, C7-13aralkyl, C6-10aryl or a hetrocyclic group selected from the class consisting of 2-furyl, 2-thienyl, 4-thiazolyl, 4-imidazolyl, 4-pyridyl, 1,3,4-thiadiazol-2-yl and 5-tetrazolyl, and the cycloalkyl, the cycloalkenyl, the aryl and the aryl ring of the aralkylgroups may have up to five substituents selected from the class consisting of C1-6alkyl, C1-6hydroxyalkyl, amino, mono- or di-C1-6alkylamino, nitro, halogen, hydroxy, C1-4alkoxy, C1-6alkylthio, cyano, carbamoyl, carboxyl, C1-6alkanoyl, C1-6alkyl-sulfonyl, C1-6alkylsufonyloxy, and C1-6alkylsulfonyloxy-C1-6alkyl;
and the C1-6alkyl, C2-6alkenyl and C2-6alkynyl defined for R1 and R2 may be substituted by halogen, hydroxyl or C1-6alkylsulfony-loxy.
and the C1-6alkyl, C2-6alkenyl and C2-6alkynyl defined for R1 and R2 may be substituted by halogen, hydroxyl or C1-6alkylsulfony-loxy.
10. A compound according to claim 9, wherein: A is phenylthio, 1-naphthylthio, 8-quinolylthio, methylthio, phenylsulfinyl, methylsulfinyl, methylsulfonyl, 4-pyridylthio, N-methyl-4-pyrid-iniothio, 2-pyrimidinylthio, ethylthio, allylthio, 2-hydroxy-benzylthio, 2-methanesulfonyloxybenzylthio, 4-hydroxybutylthio, 4-methanesulfonyloxybutyrylthio, 2-chloromethylbenzylthio, 2-hydroxyethylthio, 4-chlorobenzylthio, 4-bromobenzylthio, 4-fluorobenzylthio, 4-methylbenzylthio, 3-bromobenzylthio, 2-brom obenzylthio, 3,4,5,6-tetrafluoro-2-hydroxymethylhenzylthio, 3,4,5,6-tetrafluoro-2-methanesulfonyloxybenzylthio or 6-hydroxy-methylthio-3-cyclohexenylmethylthio.
11. A compound according to any one of claims 2 to 10, wherein: B is -NR4; R4 is hydrogen, C1-6alkyl or C6-10aryl; and E is hydrogen or carbamoyl which may be substituted by C1-6alkan-oyl or C1-6halogenoalkanoyl.
12. A compound according to claim 11, wherein: -B-E is amino, hexylamino or N1-chloroacetylureido.
13. A compound according to any one of claims 2 to 10, wherein: B is 0.
14. A compound according to claim 13, wherein E is hydrogen.
15. A compound according to claim 13, wherein E is C1-10 anoyl, C7-10aroyl, C2-7alkoxycarbonyl, C1-6alkylsulfonyl or C7-11aryloxycarbonyl.
16. A compound according to claim 13, wherein E is carbamoyl which may be substitued by C3-6alkenyl, C1-6alkyl or C6-10aryl, C1-6alkanoyl (which may further be substituted by halogen, C1-6alkylthio, C7-11aralkylthio, C6-10arylthio,benzothiazolylthio or quinolylthio).
17. A compound according to claim 13 wherein: E is carbamoyl, chloroacetylcarbamoyl, acryloylcarbamoyl, methacryloxylcarbamoyl, 3-chloro-2-methylpropionylcarbamoyl, phenylthioacetylcarbamoyl, 1-naphthylthioacetylcarbamoyl, 8-quinolylthioacetylcarbamoyl, l-naphthylcarbamoyl, 2-benzothiazolylthioacetylcarbamoyl, morpho-linocarbonyl, chloromethylcarbamoyl, 2-chloroethylcarbamoyl, (2-benzothiazolylthio)thioacetylcarbamoyl, methylthioacetylcarbam-oyl or benzylthioacetylcarbamoyl.
18. A compound of the general formula:
wherein A is halogen, N(O)mR1R2, N?R1R2R3?X?, S(O)nR1 or S?(O)mR1R2?X? where R1,R2 and R3 are each optionally substituted hydrocarbon or heterocyclic group; 2? is a counter anion; m is an integer of 0 or 1; n is an integer of 0 to 2; R1 and R2 may form a nitrogen-containing or a sulfur-containing heterocyclic ring, which may further form a condensed ring, with the adjacent nitrogen atom or sulfur atom, and these nitrogen-containing or sulfur-containing heterocyclic rings may have substituents, B is O or NR4 where R4 is hydrogen or an optionally substituted lower alkyl or aryl group, D is 2-methyl-1-propenyl group or isobutyl group, and E is hydrogen, an optionally substituted hydrocarbon or an optionally substituted acyl group;
provided that, when A is chlorine, E is an optionally substituted hydrocarbon or acyl excepting dinitrobenzoyl, or a salt thereof.
wherein A is halogen, N(O)mR1R2, N?R1R2R3?X?, S(O)nR1 or S?(O)mR1R2?X? where R1,R2 and R3 are each optionally substituted hydrocarbon or heterocyclic group; 2? is a counter anion; m is an integer of 0 or 1; n is an integer of 0 to 2; R1 and R2 may form a nitrogen-containing or a sulfur-containing heterocyclic ring, which may further form a condensed ring, with the adjacent nitrogen atom or sulfur atom, and these nitrogen-containing or sulfur-containing heterocyclic rings may have substituents, B is O or NR4 where R4 is hydrogen or an optionally substituted lower alkyl or aryl group, D is 2-methyl-1-propenyl group or isobutyl group, and E is hydrogen, an optionally substituted hydrocarbon or an optionally substituted acyl group;
provided that, when A is chlorine, E is an optionally substituted hydrocarbon or acyl excepting dinitrobenzoyl, or a salt thereof.
19. The compound according to claim 1, wherein A is N(O)mR1R2, N?R1R2R3?X?, S(O)nR1 or S?(O)mR1R2?X? where R1, R2, R3, X?, m and n are the same as defined above in claim 1.
20. The compound according to claim 19, wherein R1, R2 and R3 are each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6-cycloalkyl, C3-6cycloalkenyl, C7-13aralkyl, 5- or 6-membered heterocyclic group containing nitrogen, oxygen or/and sulfur atom or bicyclic condensed heterocyclic ring of 5- or 6-membered heterocyclic ring containing nitrogen, oxygen or/and sulfur atom with a 5- or 6-membered ring, which may be substituted, or R1 and R2 form a 4- to 7-membered nitrogen or sulfur-containing ring or bicyclic condensed heterocyclic ring with a 5-or 6-membered cyclic group, which may he substituted.
21. The compound according to claim 1, wherein A is N(O)mR1R2 in which R1 and R2 are each C-6alkyl, or together with the adjacent nitrogen atom form a pyrrolidine, piperidine, morpholine or 4-methylpiperazine, and m is 0 or 1.
22- The compound according to claim 1, wherein A is N?R1R2R2?X3 in which R1, R2 and R3 are each C1-6 alkyl, or R1 and R2 together with the adjacent nitrogen atom form a pyrrolidine, piperidine, morpholine or 4-methylpiperazine and R3 is C1-6alkyl, and X? is inorganic counter anion.
23- The compound according to claim 1, wherein A is S(O)nR1 in which R1 is C1-6alkyl which may be substituted with hydroxyl, mesyloxy or phenyl which may be further substituted with halogen, hydroxymethyl or mesyloxymethyl, C2-6alkenyl, phenyl, naphthyl, pyridyl or quinolyl, and n is 0 or 1.
24- The compound according to claim 1, wherein A is S?(O)mR1R2?X? in which R1 is C1-6alkyl and R2 is C1-6alkyl which may be substituted with phenyl, C2-6alkenyl, C2-6-alkynyl or phenyl which may be substituted with halogen or C1-6alkyl, or R1 and R2 together with the adjacent sulfur atom form tetrahydrothiophene, thioxane, dihydrobenzo[c]thiophene, hexahydrobenzo[c]thiophene, perhydrobenzo[c]thiophene, tetrahydrobenzo[c]thiophene, _ 128 _ dihydrothieno[3,4-c]pyridine, dihydrothieno[3,4-b]piradine, dihydrothieno[3,4-d]piridazine, m is 0 and X? is organic or inorganic counter anion.
25. The compound according to claim 1, wherein B is O
or NH.
or NH.
26. The compound according to claim 1, wherein D is 2-methyl-1-propenyl.
27. The compound according to claim 1, wherein E is hydrogen or C1-6alkyl.
28. The compound according to claim 1, wherein E is C1-6alkanoyl, C7-11aroyl, 5- or 6-membered heterocyclic carbonyl containing 1 to 4 of nitrogen, oxygen or/and sulfur atoms, carbamoyl, thiocarbamoyl, C6-11 arylsulfonyl, C1-6alkylsulfonyl, sulfamoyl, C2-7-alkoxycarbonyl or C7-11aryloxycarbonyl, which may be substituted.
29. The compound according to claim 1, wherein E is benzoyl; carbamoyl; C1-6alkylcarbamoyl which may be substituted with halogen; C1-6alkanoylcarbamoyl which may be substituted with halogen, C1-6alkylthio, C6-11-arylthio, C7-13aralkylthio, quinolylthio or benzothiazolylthio; C2-6alkenylcarbamoyl; C6-11-arylcarbamoyl; morpholyl; C6- 11arylsulfonyl; C1-6-alkylsulfonyl or C7-11aryloxycarbonyl .
30. The compound according to claim 1, wherein A is S?R1R2?X? wherein R1 is C1-6alkyl and R2 is C1-6alkyl which may be substituted with phenyl, or R1 and R2 together with the adjacent sulfur atom form dihydrobenzo[c]thiophene and X? is halogen anion; B is O or NH; D is 2-methyl-1-propenyl; and E is hydrogen or _ 129 _ C1-6alkanoyl which may be substituted with halogen.
31. The compound according to claim 1, which is 4-(N-chloroacetylcarbamoyloxy)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(1,3,3a,4,7,7a-hexahydrobenzo[c]thiophen-2-ylio)methyl-3-methoxycyclohexanol chloride.
32. The compound according to claim 1, which is 4-(N-chloroacetylcarbamoyloxy)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(1,3-dihydrobenzo[c]thiophen-2-ylio)methyl-3-methoxycyclohexanol chloride.
33. The compound according to claim 1, which is 4-(N'-chloroacetylureido)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(1,3-dihydrobenzo[c]thiophen-2-ylio)methyl-3-methoxycyclohexanol chloride.
34. A method of producing the compound according to claim 1 which comprises reacting a compound of the formula:
wherein B, D and E are the same as defined above in claim 1, with halogenated hydrocarbon or a compound of the formula: HNR1R2 or HSR1, and if desired, by subjecting the reaction product to oxidation, N- or S-alkylation, hydrocarbonation or acylation.
wherein B, D and E are the same as defined above in claim 1, with halogenated hydrocarbon or a compound of the formula: HNR1R2 or HSR1, and if desired, by subjecting the reaction product to oxidation, N- or S-alkylation, hydrocarbonation or acylation.
35. A pharmaceutical composition which contains a compound of the formula:
wherein A is halogen, N(O)mR1R2, N?R1R2R3?X?, S(O)nR1 or S?(O)mR1R2?X? where R1,R2 and R3 are each optionally substituted hydrocarbon or heterocyclic group; X? is a counter anion; m is an integer of 0 or 1; n is an integer of 0 to 2; R1 and R2 may form a nitrogen-containing or a sulfur-containing heterocyclic ring, which may further form a condensed ring, with the adjacent nitrogen atom or sulfur atom, and these nitrogen-containing or sulfur-containing heterocyclic rings may have substituents, B is O or NR4 where R4 is hydrogen or an optionally substituted lower alkyl or aryl group, D is 2-methyl-1-propenyl group or isobutyl group, and E is hydrogen, an optionally substituted hydrocarbon or an optionally substituted acyl group, or a salt thereof and a pharmaceutically acceptable carrier of excipient therefor.
wherein A is halogen, N(O)mR1R2, N?R1R2R3?X?, S(O)nR1 or S?(O)mR1R2?X? where R1,R2 and R3 are each optionally substituted hydrocarbon or heterocyclic group; X? is a counter anion; m is an integer of 0 or 1; n is an integer of 0 to 2; R1 and R2 may form a nitrogen-containing or a sulfur-containing heterocyclic ring, which may further form a condensed ring, with the adjacent nitrogen atom or sulfur atom, and these nitrogen-containing or sulfur-containing heterocyclic rings may have substituents, B is O or NR4 where R4 is hydrogen or an optionally substituted lower alkyl or aryl group, D is 2-methyl-1-propenyl group or isobutyl group, and E is hydrogen, an optionally substituted hydrocarbon or an optionally substituted acyl group, or a salt thereof and a pharmaceutically acceptable carrier of excipient therefor.
36. A method of inhibiting angiogenesis or treating tumor which comprises administering to mammal a therapeutically effective amount of a compound of the formula:
wherein A is halogen, N(O)mR1R2, N?R?R2R3?X?, S(O)nR1 or S?(O)mR1R2?X? where R1, R2 and R3 are each optionally substituted hydrocarbon or heterocyclic group; X3 is a counter anion; m is an integer of 0 or 1; n is an integer of O to 2; R1 and R2 may form a nitrogen-containing or a sulfur-containing heterocyclic ring, which may further form a condensed ring, with the adjacent nitrogen atom or sulfur atom, and these nitrogen-containing or sulfur-containing heterocyclic rings may have substituents, B is O or NR4 where R4 is hydrogen or an optionally substituted lower alkyl or aryl group, D is 2-methyl-1-propenyl group or isobutyl group, and E is hydrogen, an optionally substituted hydrocarbon or an optionally substituted acyl group, or a pharmaceutically acceptable salt, optionally with a pharmaceutically acceptable carrier or excipient therefor.
wherein A is halogen, N(O)mR1R2, N?R?R2R3?X?, S(O)nR1 or S?(O)mR1R2?X? where R1, R2 and R3 are each optionally substituted hydrocarbon or heterocyclic group; X3 is a counter anion; m is an integer of 0 or 1; n is an integer of O to 2; R1 and R2 may form a nitrogen-containing or a sulfur-containing heterocyclic ring, which may further form a condensed ring, with the adjacent nitrogen atom or sulfur atom, and these nitrogen-containing or sulfur-containing heterocyclic rings may have substituents, B is O or NR4 where R4 is hydrogen or an optionally substituted lower alkyl or aryl group, D is 2-methyl-1-propenyl group or isobutyl group, and E is hydrogen, an optionally substituted hydrocarbon or an optionally substituted acyl group, or a pharmaceutically acceptable salt, optionally with a pharmaceutically acceptable carrier or excipient therefor.
37. An use of a compound of the formula:
wherein A is halogen, N(O)mR1R2, N?R1R2R3?X?, S(O)nR1 or S?(O)mR1R2?X? where R1,R2 and R3 are each optionally substituted hydrocarbon or heterocyclic group; X? is _ 132 _ counter anion; m is an integer of 0 or 1; n is an integer of 0 to 2; R1 and R2 may form a nitrogen-containing or a sulfur-containing heterocyclic ring, which may further form a condensed ring, with the adjacent nitrogen atom or sulfur atom, and these nitrogen-containing or sulfur-containing heterocyclic rings may have substituents, B is O or NR4 where R4 is hydrogen or an optionally substituted lower alkyl or aryl group, D is 2-methyl-1-propenyl group or isobutyl group, and E is hydrogen, an optionally substituted hydrocarbon or an optionally substituted acyl group, or a pharmaceutically acceptable salt, optionally with a pharmaceutically acceptable carrier or excipient therefor in the preparation of a composition for inhibiting angiogenesis or treating tumor.
wherein A is halogen, N(O)mR1R2, N?R1R2R3?X?, S(O)nR1 or S?(O)mR1R2?X? where R1,R2 and R3 are each optionally substituted hydrocarbon or heterocyclic group; X? is _ 132 _ counter anion; m is an integer of 0 or 1; n is an integer of 0 to 2; R1 and R2 may form a nitrogen-containing or a sulfur-containing heterocyclic ring, which may further form a condensed ring, with the adjacent nitrogen atom or sulfur atom, and these nitrogen-containing or sulfur-containing heterocyclic rings may have substituents, B is O or NR4 where R4 is hydrogen or an optionally substituted lower alkyl or aryl group, D is 2-methyl-1-propenyl group or isobutyl group, and E is hydrogen, an optionally substituted hydrocarbon or an optionally substituted acyl group, or a pharmaceutically acceptable salt, optionally with a pharmaceutically acceptable carrier or excipient therefor in the preparation of a composition for inhibiting angiogenesis or treating tumor.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP22651489 | 1989-08-31 | ||
| JP226514-1989 | 1989-08-31 | ||
| JP5775290 | 1990-03-08 | ||
| JP057752-1990 | 1990-03-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2024306A1 true CA2024306A1 (en) | 1991-03-01 |
Family
ID=26398821
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002024306A Abandoned CA2024306A1 (en) | 1989-08-31 | 1990-08-30 | Cyclohexanol derivatives, production and use thereof |
Country Status (4)
| Country | Link |
|---|---|
| US (1) | US5180735A (en) |
| EP (1) | EP0415294A3 (en) |
| KR (1) | KR910004587A (en) |
| CA (1) | CA2024306A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0797988A2 (en) | 1993-07-19 | 1997-10-01 | Angiotech Pharmaceuticals, Inc. | Anti-angiogenic compositions and methods of use |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1333363C (en) * | 1988-01-19 | 1994-12-06 | Judah Folkman | Angiogenesis inhibitor comprising fumagillin |
| PH26256A (en) * | 1988-08-12 | 1992-04-01 | Fujisawa Pharmaceutical Co | Oxaspiro [2,5] octane derivative |
| US4954496A (en) * | 1988-08-12 | 1990-09-04 | Fujisawa Pharmaceutical Company, Ltd. | Cyclohexane derivatives and pharmaceutical compositions |
-
1990
- 1990-08-25 EP EP19900116309 patent/EP0415294A3/en not_active Withdrawn
- 1990-08-29 US US07/575,559 patent/US5180735A/en not_active Expired - Fee Related
- 1990-08-30 CA CA002024306A patent/CA2024306A1/en not_active Abandoned
- 1990-08-31 KR KR1019900013743A patent/KR910004587A/en not_active IP Right Cessation
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0797988A2 (en) | 1993-07-19 | 1997-10-01 | Angiotech Pharmaceuticals, Inc. | Anti-angiogenic compositions and methods of use |
| EP2226085A1 (en) | 1993-07-19 | 2010-09-08 | Angiotech Pharmaceuticals, Inc. | Anti-angiogenic compositions and methods of use |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0415294A2 (en) | 1991-03-06 |
| KR910004587A (en) | 1991-03-29 |
| EP0415294A3 (en) | 1991-06-12 |
| US5180735A (en) | 1993-01-19 |
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| Date | Code | Title | Description |
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| FZDE | Discontinued |